
==== Front
Curr Neuropharmacol
Curr Neuropharmacol
CN
Current Neuropharmacology
1570-159X
1875-6190
Bentham Science Publishers

38288836
CN-22-2217
10.2174/1570159X22666240128102039
Medicine, Neurology, Pharmacology, Neuroscience
Astrocytes and Memory: Implications for the Treatment of Memory-related Disorders
Wang Juan 1#
Cheng Ping 1#
Qu Yan 1
Zhu Guoqi 1*
1 Key Laboratory of Xin’an Medicine, The Ministry of Education and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei 230012, China
* Address correspondence to this author at the Key Laboratory of Xin’an Medicine, the Ministry of Education and Key Laboratory of Molecular Biology (Brain diseases), Anhui University of Chinese Medicine, Hefei 230012, China; Fax: 8655168129028; E-mail: guoqizhu@gmail.com
# These authors contributed equally to this work.
29 1 2024
2024
22 13 22172239
06 9 2023
29 10 2023
© 2024 The Author(s). Published by Bentham Science Publishers
2024
The Author(s)
https://creativecommons.org/licenses/by/4.0/ © 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode.
Memory refers to the imprint accumulated in the brain by life experiences and represents the basis for humans to engage in advanced psychological activities such as thinking and imagination. Previously, research activities focused on memory have always targeted neurons. However, in addition to neurons, astrocytes are also involved in the encoding, consolidation, and extinction of memory. In particular, astrocytes are known to affect the recruitment and function of neurons at the level of local synapses and brain networks. Moreover, the involvement of astrocytes in memory and memory-related disorders, especially in Alzheimer’s disease (AD) and post-traumatic stress disorder (PTSD), has been investigated extensively. In this review, we describe the unique contributions of astrocytes to synaptic plasticity and neuronal networks and discuss the role of astrocytes in different types of memory processing. In addition, we also explore the roles of astrocytes in the pathogenesis of memory-related disorders, such as AD, brain aging, PTSD and addiction, thus suggesting that targeting astrocytes may represent a potential strategy to treat memory-related neurological diseases. In conclusion, this review emphasizes that thinking from the perspective of astrocytes will provide new ideas for the diagnosis and therapy of memory-related neurological disorders.

Keywords

Astrocyte
memory
memory-related disorder
synaptic plasticity
neuronal networks
Alzheimer’s disease
PTSD
==== Body
pmc1 INTRODUCTION

Over the last few decades, research activities in the field of memory have predominantly focused on neurons. However, the brain is a highly evolved organ and not just a collection of neurons and neural circuits. Consequently, it is necessary to consider the multiple types of constituent cells and their interactions, as these are crucial for the functionality of the entire system. Previously, astrocytes were not thought to actively participate in the processing of memory, possibly because they lack electrical excitability and have no direct connections with the surrounding sensory organs. However, since the 1990s, studies have shown that astrocytes, as an important aspect of the ‘tripartite synapse’, not only provide stable support for neurons but also sense synaptic activity, respond to surrounding synaptic activity through Ca2+ signals and then regulate neuronal activity via feedback and the release of neurotransmitters [1-4]. The astrocyte membrane features a variety of ion channels, transporters, ion pumps and receptors; collectively, these structures enable astrocytes to sense the activities of the surrounding neurons, regulate the balance of extracellular potassium ions, rapidly clear neurotransmitters in the synaptic gap, and provide metabolic support for neurons [5]. In addition, astrocytes can also release various neuroactive substances, including glutamate, ATP, γ-aminobutyric acid (GABA), and D-serine; these substances may play roles in regulating neuronal synaptic plasticity [6] (Fig. 1).

Astrocytes are widely recognized to perform prominent roles in synaptogenesis and brain synaptic plasticity [7], and different steps or processes of memory [8, 9]. Moreover, astrocytes are known to participate in memory-related disorders, including Alzheimer’s disease (AD) [10, 11], post-traumatic stress disorder (PTSD) [12], and addiction [13]. With the development and application of various technologies, such as designer receptors exclusively activated by designer drug techniques [14], it is now possible to manipulate astrocytes in a highly dynamic manner. Furthermore, astrocytes can be monitored in real-time in the brain, thus providing opportunities for in-depth research targeting the role of astrocytes in different stages of memory [15, 16]. In this review, we demonstrate the unique contributions of astrocytes to synaptic plasticity and neuronal networks and discuss the role of astrocytes in various forms of memory processing. In addition, we also explore the pathogenesis and treatment of memory-related disorders, including AD, brain aging, addiction, and PTSD, from the perspective of astrocytes. This review highlights important implications for the treatment of memory-related neurological diseases.

2 ASTROCYTES AND CA2+ SIGNALING

Unlike neurons, astrocytes are mostly electrically silent cells. Their resting membrane potential rarely deviates from the K+ balance potential by more than a few millivolts, and there is no evidence that astrocytes exhibit propagating or gradient electrical signals that are similar to the electrical signals in neurons [17]. In the absence of obvious electrical signals, the excitability of astrocytes is mainly based on the highly spatiotemporal fluctuations of intracellular Ca2+ concentrations which are dependent on the cell membrane and intracellular channels [18]. Therefore, understanding intracellular Ca2+ signaling in astrocytes is crucial if we are to decode the functionality of astrocytes in the central nervous system (CNS).

With the development of advanced optical technologies such as two-photon excitation fluorescence imaging and sensitive gene coding indicators, Ca2+ signaling has become the focus for studying molecular and cellular aspects of astrocytes [19]. In the brain, Ca2+ events can occur spontaneously in the astrocytes [20-23]; these events can also be triggered by external physical stimuli [5, 23-25]. Astrocytes are known to express a large number of neurotransmitter receptors, many of which are G protein-coupled receptors (GPCR). Neurotransmitters can stimulate an increase in the intracellular concentration of Ca2+ in astrocytes; this occurs via the release of Ca2+ from the endoplasmic reticulum through the IP3 receptor [26-28]. In astrocytes, Ca2+ signaling transduction is dependent on type 2 IP3 receptor (IP3R2). However, even in the absence of IP3R2, astrocytes can still exhibit different types of Ca2+ fluctuations [29]. Ca2+ signals in astrocytes can be spatially confined to a single subcellular domain or generated in a coordinated manner by a number of astrocytes [30]. Super-resolution imaging has revealed many ring-like structures in the spongiform domain of astrocytes; these structures are referred to as ‘nodes’. These ‘nodes’ are morphological structures that carry Ca2+ transients on the tripartite synapse [31].

Ca2+ release in astrocytes occurs in a slow and spatially distributed manner. These events are thus considered to be too slow to participate in the processing of information in real-time. However, the application of advanced imaging and analysis techniques in recent studies has shown that the Ca2+ events that occur in parts of the microdomain of astrocytes are ultra-fast and last less than 300 ms; this is almost as fast as those of neurons (~208 ms) [32, 33]. In addition, astrocytes can also encode information by Ca2+ event patterns. Imaging data has shown that astrocytes possess a behavioral-dependent hot spot of Ca2+ activity, which remains stable for a few days and may represent a memory imprint [32]. In addition, the pattern of Ca2+ in astrocytes (that is, the total area, number, and duration of Ca2+ events) changes in each imaging frame [34]. Therefore, the spatial pattern of astrocyte activity can change almost instantaneously, thus implying that astrocytes may play an important role in the processing of information [19].

3 ASTROCYTES CAN INFLUENCE SYNAPTIC PLASTICITY

Synaptic connections can undergo several types of alterations, including formation, elimination, enhancement, and weakening [35, 36]. For example, the growth of new synaptic connections and the recombination of existing synaptic connections are considered key mechanisms for acquiring and stabilizing new memories [37]. Synaptic plasticity is used to describe changes in the strength of synaptic connections in the process of experiencing events and neural activities [38]. Such changes in the strength of synaptic connections are not only regulated by bidirectional communication between presynaptic and postsynaptic neurons, but also by interactions between neurons and their associated glia [39]. Astrocytes are important regulators of synaptic plasticity. Here, we discuss the important contribution of astrocytes to synaptic plasticity (Fig. 1).

3.1 Long-term Potentiation (LTP)

LTP refers to the long-term enhancement of synaptic efficacy caused by high-frequency stimuli (HFS) [40]. LTP can be further divided into early LTP (E-LTP) and late LTP (L-LTP). E-LTP is usually induced by a single HFS, while L-LTP is induced by repeated HFS at second intervals [41, 42]. Decoding the Ca2+ signals produced by astrocytes is the key to understanding the role of these cells in LTP. The IP3R2 is considered to be the main receptor regulating Ca2+ signal transduction in astrocytes. LTP and glial transmission depend on Ca2+ release by IP3Rs in astrocytes [43]. In a previous study, Navarrete et al. found that Ca2+ signaling in astrocytes is necessary for choline-induced synaptic plasticity. These authors also found that choline-induced LTP required Ca2+ levels to increase in astrocytes, thus stimulating astrocytes to release glutamate and activate metabotropic glutamate receptors (mGluRs). When astrocyte Ca2+ signals were blocked, choline-induced LTP was not detected in IP3R2 knockout (KO) mice and wild-type mice [44]. In addition, Liu et al. used astrocyte IP3R2 KO mice, Mas-related gene A1 (MrgA1+) mice, and IP3R2 conditional KO mice to further investigate the role of astrocyte Ca2+ signals in synaptic plasticity. These authors showed that astrocyte IP3R2-dependent Ca2+ signals were critical for L-LTP rather than E-LTP. This process is mediated by brain-derived neurotrophic factor (BDNF) released by the astrocytes. Moreover, inhibiting IP3R2 signals or BDNF production in astrocytes damaged remote memory, while the deletion of BDNF in neurons led to defects in memory acquisition and retrieval [45]. In another study, Requeie et al. found that astrocytes mediated a new form of synaptic plasticity in the dopamine neurons within the ventral tegmental area (VTA) [46]. These authors also found that the burst discharge of a single dopamine neuron induced LTP in the excitatory synapses of adjacent dopamine neurons in the VTA in a manner that depended on the IP3R2-mediated increase of Ca2+ in astrocytes. Further research found that LTP needed to be co-located in the same astrocyte mediated by endogenous cannabinoid CB1 and dopamine D2 receptors and required the activation of presynaptic metabotropic glutamate receptor (mGluR1). The activation of astrocytes through chemical genetics has been shown to increase the burst discharge of DA neurons in the VTA [46].

Astrocytes mediate LTP by releasing fast mediators that change synaptic function. For example, the induction of NMDA receptor (NMDAR)-dependent LTP in hippocampal CA1 excitatory synapses requires the transient release of D-serine from local astrocytes [47]. D-serine is a physiological co-agonist of NMDAR and plays an important role in synaptic plasticity, learning, and memory [48, 49]. The mechanisms responsible for the direct release of D-serine from astrocytes have yet to be determined. Initially, it was thought that astrocytes released L-serine and L-serine, which were then shuttled to neurons, thus providing fuel for neurons to synthesize D-serine [50]. However, it cannot be denied that the induction of LTP in the hippocampus requires Ca2+ signals in astrocytes and D-serines [43, 47, 51]. The authors of a recent study claimed that astrocytes might act as the target cells for the activity-dependent production of D-serine and that the activation of astrocytic rather than neuronal α7-nicotine acetylcholine receptor (α7nAChR) promotes the occupation of binding sites for the D-serine-mediated activation of NMDAR [51]. In addition, astrocytes can also synthesize D-serine and release it through the Best1 calcium channel [52]. In another study, Huang et al. identified a transcription factor, nuclear factor I-A (NFIA), that could bind to DNA and regulate gene expression. The deletion of NFIA selectively reduced the morphological complexity and Ca2+ activity of hippocampal astrocytes. Furthermore, Theta burst stimulation (TBS)-induced LTP in the hippocampal Schaffer collaterals pathway was significantly inhibited in NFIA conditional KO mice; with the reduction of Ca2+-dependent D-serine, these mice showed impairment of working memory. In contrast, this impairment of LTP could be repaired by restoring astrocyte Ca2+ or by administering exogenous D-serine [53].

L-lactic acid is also known to be released by astrocytes and has been proven to play a key role in hippocampal LTP [54]. In the brain, metabolic coupling is considered a key mechanism for the active interaction between astrocytes and neurons in order to respond to neuronal activity. Glycogen stored in astrocytes is metabolized to L-lactic acid, which is then shuttled to neurons when energy is required [55-57]. Suzuki et al. found that the pharmacological inhibition of glycogen breakdown during LTP induction can disrupt the maintenance of hippocampal LTP, while the supplementation of L-lactate can rescue this damage [54]. Therefore, the availability of L-lactic acid is necessary for maintaining LTP.

Astrocytes can also affect LTP via the cannabinoid receptor type 1 (CB1R) signaling pathway. CB1R has been identified as a specific type of cannabinoid receptor and is expressed at high levels in neurons throughout the entire brain [58]. CB1R is also functionally expressed in astrocytes. The activation of CB1R stimulates the release of Ca2+-dependent glutamate and enhances synaptic transmission at the hippocampal CA3-CA1 synapse [59]. The supply of D-serine mediated by astrocyte CB1 receptor is a necessary condition for hippocampal LTP [60]. Mutant mice lacking astrocytic CB1R (GFAP-CB1-KO) generated an abnormal form of hippocampal LTP in the CA3-CA1 synapse that could be rescued by the supplementation of exogenous D-serine [60]. Astrocytes express a variety of receptors that transmit signals through the second messenger, cAMP. Zhou et al. developed a method that used light to activate adenylate cyclase to promote the levels of cAMP in astrocytes in vivo. These authors found that increasing the levels of cAMP in hippocampal astrocytes at different time points was sufficient to induce LTP in peripheral neurons and promote the formation of memory and that this effect could be interrupted by blocking NMDAR-dependent synaptic plasticity [61].

Very recent research demonstrated that astrocytes express Piezo1, a mechanically gated cation channel that can mechanically regulate Ca2+ signals and ATP release in astrocytes. The knockout of Piezo1 in astrocytes led to the impairment of hippocampal LTP and neurogenesis. In addition, Piezo1-deficient mice showed impairments of spatial working memory. In contrast, the overexpression of Piezo1 in astrocytes was shown to rescue the damaged LTP and memory impairment [62]. Similarly, the occurrence of LTP can also affect the state of astrocytes. For example, Henneberger et al. found that high-frequency stimulation (HFS) of the Schafer collateral of the hippocampus induced a reduced volume in the perisynaptic astroglial processes (PAPs), promoted the withdrawal of PAPs on the nanoscale, thereby promoting an overflow of extracellular glutamate and enhancing the activation of NMDAR [63]. This study suggested that memory traces in a synapse can alter signal processing in multiple adjacent connections. In addition, continuous synaptic strengthening can promote the microdomain of astrocytes to transform initially internalized (pro) brain-derived neurotrophic factor (proBDNF) into mature BDNF (mBDNF) to achieve synaptic recycling. proBDNF and mBDNF are both known to enhance TrkB signals via adaptive molecular mechanisms to promote the maintenance of LTP and the consolidation of memory [64].

3.2 Long-term Depression (LTD)

LTD refers to a long-term reduction in synaptic transmission caused by low-frequency stimuli (LFS) [65]. Astrocytes can regulate NMDAR-dependent LTD by regulating endogenous cannabinoids and D-serine. For example, Han et al. found that exposure to exogenous cannabis in vivo could activate the CB1R on astrocytes, increase the extracellular levels of glutamate, further activate the NR2B subunit of NMDAR, and promote the endocytosis of postsynaptic AMPAR. These events ultimately mediate the induction of LTD in the hippocampal CA3-CA1 synapse and participate in working memory in vivo [66]. The analysis of brain slices in vitro showed that the neuronal release of endogenous cannabinoids could activate the CB1R on astrocytes in the hippocampal CA1 area, induce an increase of Ca2+ in astrocytes, stimulate the release of glutamate, and then activate the presynaptic metabolic mGluRs to induce LTP in the CA3-CA1 synapse [59, 67].

D-serine is also known to be involved in NMDAR-dependent LTD in the hippocampus. Two recent studies support the view that the release of D-serine by astrocytes is necessary for LTD. For example, Pinto-Duarte et al. applied LFS (1 Hz) to induce NMDAR-dependent LTD in the Schaffer collateral. Compared with wild-type mice, astrocyte IP3R2 KO mice had impaired LTD maintenance and exhibited impairments in remote recognition memory and fear memory. The exogenous supplementation of D-serine was shown to rescue the impairment of hippocampal LTD [68]. In a second study, Best1 KO mice exhibited reduced NMDAR function, simultaneously impaired LTD, and α1 adrenergic receptor-dependent heterosynaptic LTD. These impairments could be rescued by the specific expression of Best1 in the hippocampal astrocytes or the enhancement of NMDAR function by supplementation with D-serine [52].

Navarrete et al. found that LFS-induced LTD in the hippocampal Schaefer collateral could enhance communications between neurons and astrocytes. Astrocytes provide sufficient glutamate at the postsynaptic membrane responsible for CA3-CA1 synaptic transmission. This mechanism requires Ca2+ activity in astrocytes and SNARE-dependent vesicular release. In addition, p38α mitogen-activated protein kinase (MAPK) activity in astrocytes, but not in neurons, is necessary for hippocampal LTD; the selective deletion of p38α in astrocytes blocks the expression of LTD [69]. This study challenged the view that hippocampal NMDAR-dependent LTD is reliant on direct communications between presynaptic glutamate release and postsynaptic NMDAR activation; rather, the authors proposed that the activation of astrocytes is required for LTD in the hippocampus.

Insulin-like growth factor-1 (IGF-1) is a polypeptide that has a molecular structure similar to that of insulin; this polypeptide is known to play roles in growth, development, learning, and memory [70]. Noriega-Prieto et al. recently found that IGF-1 induced LTP in pyramidal neurons of layer II/III of the barreled cortex in mice and that this was caused by the long-term inhibition of inhibitory synaptic transmission. Further research found that this cortical LTD was caused by the activation of astrocytes via the IGF-1 receptors (IGF-1Rs), thereby regulating the performance of behavioral tasks related to cortical sensory information processing [71]. Collectively, these data indicate that astrocytes also perform critical functions in LTD, either by mediating neuron-neuron communication or by directly activating postsynaptic glutamate receptors.

3.3 Spike-time-dependent Plasticity (STDP)

STDP is a form of Hebb long-term synaptic plasticity with rich computational properties [72]. In STDP, the order and relative millisecond time of presynaptic and postsynaptic-synaptic excitations determine the direction and amplitude of synaptic changes. Once the presynaptic neuron is stimulated for a short period of time before the postsynaptic neuron is excited, and this paired excitation is repeated multiple times, the synaptic efficacy of the synapse is enhanced in a process known as time-dependent LTP (t-LTP); time-dependent LTD (t-LTD) is induced when these events occur in the opposite order [72]. This type of plasticity requires the participation of astrocytes. For example, the activity of astrocytes is directly involved in the initiation and termination of STDP. Presynaptic t-LTD in the hippocampal CA3-CA1 synapse of mice has been shown to be converted into t-LTP as the animal develops. This form of t-LTP is expressed in the presynaptic CA3-CA1 synapse and needs to activate presynaptic mGluR5 instead of NMDARs. For this to occur, it is essential that adenosine and glutamate are released by astrocytes to activate presynaptic adenosine type 1 receptors (A1Rs) and mGluRs to mediate the conversion from presynaptic t-LTD to t-LTP [73]. In addition, adenosine and astrocytes determine the development of t-LTD in the sensory cortex. L4-L2/3 synapses in the mouse sensory cortex (S1) exhibit a presynaptic form of t-LTD from birth to the fourth week after birth; this form of t-LTD can be completely rescued by antagonizing the type 1 adenosine receptor (A1R). The adenosine-mediated loss of t-LTD is most likely induced by astrocytes [74]. In a previous study, Min et al. reported that in the developing cortex, endogenous cannabinoid-mediated t-LTD required Ca2+ signals in the astrocytes. During the induction of t-LTD, astrocytes responded to the transient increase and broadening of Ca2+ signals; this increase was dependent on the activation of CB1Rs [75].

3.4 Synaptic Remodeling

In addition to synaptic plasticity, astrocytes can also influence the formation of new synapses and the removal of old synapses. Long-term changes in synaptic efficacy are also accompanied by changes in synaptic structure, including alterations in the size of existing synapses, the formation of new synapses, and the removal of old synapses. Astrocytes are the main driving force of synaptogenesis. Thromboreactive protein (TSP) is secreted by astrocytes and is known to participate in synaptogenesis. During development, astrocytes up-regulate the release of TSP [76], which binds and activates its homologous neuronal receptor α2δ-1 to exert synaptic effects. Importantly, the TSP-mediated activation of α2δ-1 is necessary and sufficient for synaptogenesis and is also related to an increase in postsynaptic dendritic spine regeneration [77]. Although the mechanisms by which astrocytes can control synaptic formation by secreting proteins are relatively well known, the association between astrocytes and synapses remains unclear. In a recent study, Takano et al. used a chemical genetics method based on the cell surface fragment complementation strategy Split TurboID to identify the proteome enriched at the astrocyte-neuron junction in vivo [78]. These authors found that neuronal cell adhesion factor (NRCAM) is expressed by cortical astrocytes located on excitatory and inhibitory synapses and that this form of NRCAM can form complexes with gephyrin in neurons; this is a key factor in the maintenance of inhibitory synapses. In adult mice, the specific knockout of NRCAM in astrocytes was found to reduce the number of cortical inhibitory synapses; this led to a significant reduction in the inhibitory synaptic function but had little impact on excitatory synapses [78].

The phagocytosis of astrocytes is important for maintaining normal synaptic connections and plasticity in the hippocampus [79]. Astrocytes can constantly eliminate excessive and unnecessary excitatory synapse connections; this mechanism was previously verified in a MEGF10 knockout mouse model. These mice possessed astrocytes that were deficient in phagocytosis of the MEGF10 receptor; experiments showed that the elimination of the excitatory synapse was reduced in these mice, thus resulting in excessive and functionally impaired synaptic accumulation. Finally, MEGF10 knockout mice showed deficits in long-term synaptic plasticity and exhibited impaired hippocampal memory formation [80].

Astrocytes can also work with microglia to promote synaptic elimination. The interleukin-1 family cytokine, interleukin-33 (IL-33), is produced by astrocytes during development. IL-33 predominantly sends signals to microglia under physiological conditions to promote the development of microglial synaptic phagocytosis and neural circuits [81]. In addition, IL-33 is known to be secreted by astrocytes to mediate synaptic steady-state plasticity in the CA1 subregion; blocking the activity of pyramidal neurons in the CA1 subregion will selectively increase the expression and secretion of IL-33 by astrocytes. Blocking IL-33 and its receptor signal transduction can inhibit the steady synaptic plasticity of hippocampal CA1 pyramidal neurons [82]. In a previous study, Koeppen et al. found that astrocytic ephrin-B1 acts as a regulator of adult hippocampal synaptogenesis and learning behavior. The specific deletion of ephrin-B1 in astrocytes was found to increase the density of excitatory synapses and immature dendritic spines in the mouse hippocampal CA1, thus enhancing the memory of contextual fear. In contrast, the overexpression of ephrin-B1 led to the loss of the dendritic spine and impairment of contextual memory. This study revealed that astrocytic ephrin-B1 regulates long-term memory by limiting the formation of new synapses in the hippocampus [83].

4 ASTROCYTES REGULATE THE ACTIVITY OF NEURAL NETWORKS

4.1 Network Rhythm

There are several rhythmic oscillations in the brain caused by neuronal synchronization, including delta (< 4 Hz), theta (4-12 Hz), alpha (8-12 Hz), beta (12-20 Hz), and gamma oscillations (20-100 Hz). These oscillations are closely related to the encoding, consolidation, and retrieval of memory. It has been reported that astrocytes regulate neuronal oscillations in different brain regions in a variety of ways. In the hippocampus, the activation of astrocytes can specifically reduce the power of gamma oscillations in an ATP-dependent manner [84]. In the cortical area, astrocytes contribute to the generation of slow wave oscillations (< 1 Hz) [85]. The dominant state of slow wave oscillations involves a neocortex rhythm that is characterized by synchronous neuronal discharge, a process is related to sleep and memory processes [86]. Poskanzer et al. found that the activation of astrocytes can regulate the transition of cortical state in vivo. These authors found that the Ca2+ activity of astrocytes was transferred to the dominant state of slow-wave oscillations prior to the spontaneous circuit and that this state of slow-wave oscillations could be induced in the local neural network via the optogenetic activation of astrocytes; furthermore, the activation of astrocytes could induce a local increase in extracellular glutamate, thereby increasing the firing of synergistic neurons [85]. This astrocytic input acts as a guiding synchronization signal for neurons and triggers the cortical circuit to switch to the dominant state of slow-wave oscillation.

Gamma oscillations caused by sensory inputs within different ranges of the cortical oscillation spectrum are considered to represent the foundation of cortical information processing. In a recent study, Lines et al. showed that astrocytes regulate sensory-induced neural network activities [24]. The response of astrocytes in the primary somatosensory cortex to sensory stimuli was dependent on an increase in Ca2+ signaling. Sensory stimuli have been shown to cause a transient increase in neuronal network activity within the gamma range; this was followed by a decline to the steady-state phase that occurred simultaneously with a delayed Ca2+ response in the astrocytes [24]. Further research showed that the activation of cortical astrocytes by specific chemical and genetic factors could reduce the gamma activity induced by sensation. However, increased levels of gamma activity were detected in transgenic mice exhibiting astrocytes with impaired Ca2+ activity [24]. This study showed that the activity of astrocytes was able to control the size and dynamic range of sensory-evoked gamma activity under sensory information processing.

In another study, Lee et al. found that astrocytes contribute to gamma oscillations and recognition memory. By performing electrocorticography recording in mice expressing tetanus neurotoxin in their astrocytes, the authors found that gamma oscillations were significantly reduced and that this was accompanied by the impaired recognition of new objects [87]. Consistent with this study, the injection of glial toxin (L-AAA) into the medial prefrontal cortex (mPFC) of experimental rats lead to a reduction in the number of astrocytes, further resulting in a reduction in gamma and other powers, and impaired cognitive flexibility [88]. In addition, signals from astrocytes are known to support theta wave synchronization in the hippocampus and prefrontal cortex; this mechanism is important for cognitive function [89]; this study used a dnSNARE mouse model to conduct electrophysiology and behavioral analysis to investigate the impact of astrocyte-derived glial transmitters on cognition (Fig. 2). Blocking the release of glial transmitters in astrocytes was shown to trigger the basic desynchronization of theta oscillations between the dorsal hippocampus and the medial prefrontal cortex in mice. This form of desynchronization in these specific brain regions is accompanied by poor performance in cognitive tasks [89]. In contrast, supplementing D-serine was shown to restore hippocampal prefrontal theta synchronization and save spatial memory and long-term recognition memory in dnSNARE mice [89]. Finally, a recent study showed that astrocytes in the mPFC could regulate the balance between inhibition and excitability in the neural network that controls decision-making [90]. By recording the local field potential in the mPFC, researchers found that knocking out the GABAB receptor (GFAP/PFC) in astrocytes in the mPFC led to a reduction in the gamma oscillation activity of cortical neurons; this also caused damage to working memory. The activation of astrocytes by Gq-coupled melanopsin was shown to restore gamma oscillation activity and working memory deficit [90]. These authors revealed that astrocytes may play a central role in controlling the inhibition of cerebral cortex circuits; furthermore, this provides a new mechanism for the processing of cortical information.

4.2 Neural Circuits

The human brain consists of hundreds of billions of neurons; these are interconnected to form special neural circuits, thus making the brain a powerful form of ‘biological computer’ [91]. Astrocytes are known to play an important regulatory role in the brain circuit, including different aspects of neurophysiology that are related to brain function. For example, Martin et al. found that astrocytes in the medial amygdala (CeM) can determine the synaptic and behavioral output of the amygdala circuit; furthermore, the chemical activation of astrocytes in the CeM can specifically inhibit excitatory input and enhance inhibitory input [92]. In addition, the latest research by Serra et al. identified a specific neuron-astrocyte circuit in the nucleus accumbens (NAc) [93]. These authors found that selective light stimulation of major glutamate inputs (such as the prefrontal cortex, basolateral amygdala and ventral hippocampus) induced the specific activation of astrocytic subsets in the NAc; this was inconsistent with the normal pattern of glutamate innervation, thus revealing the existence of synaptic-specific neuron-astrocyte circuits in the NAc [93]. Excitatory projections from the entorhinal cortex to the dentate gyrus (DG) are known to play an important role in the coding of memory [94]. A previous study demonstrated that the projection of the perforating pathway on hippocampal dentate granule cells (GCs) is regulated by astrocytes and that this effect is mediated by sensitive NMDAR and involves the increased release of synaptic transmitters [95]. Atypical presynaptic NMDARs (preNMDARs) can be activated by astrocytes and participate in the specific control of cortical hippocampal excitatory connections between the entorhinal cortex and the DG [96]. These preNMDARs contain a GluN3a subunit, have low sensitivity to Mg2+ and functionally enhance the probability of releasing medial pathway (MPP) inputs to GC dendrites. PreNMDARs also control the dynamic range of LTP in MPP-GC synapses via a process that requires Ca2+ signaling in astrocytes [96]. This study showed that this circuit-specific regulatory mechanism of astrocytes may be of great significance for changes in memory processing and pathological conditions.

Compared with neurons, astrocytes do not have long-distance connections and are considered to function locally. However, recent studies highlight the fact that astrocytes may regulate long-distance neurons via gap junction-related astrocyte networks. For example, Zhao et al. found that the optogenetic activation of astrocytes in the left primary motor cortex of mice could alleviate kainic acid-induced seizures on the right side of the brain and also influenced the electrical activity of neurons in the right primary motor cortex in which more than 80% of high-frequency (> 5 Hz) firing pyramidal neurons were suppressed [97]. In addition, astrocytes can exert an important impact on the long-distance projection of neurons. For example, Kol et al. reported that astrocytes promote the formation of remote memory by regulating hippocampal cortical communication during learning [98]. By specifically expressing the Gi-coupled design receptor hM4Di in hippocampal CA1 astrocytes, the activation of astrocytes during learning was shown to damage remote memory rather than short-term memory and reduced activity in the anterior cingulate cortex (ACC). In addition, Gi-induced activation of astrocytes was reported to destroy the communication links between CA3 and CA1, weaken the activation of ACC neurons induced by training, and damage remote memory [98]. Astrocytes not only regulate neural activity locally (at the synaptic level); they also regulate neural activity remotely via neural circuits. Schema memory is a concept of cognitive psychology and represents an interactive knowledge framework that is stored in long-term memory in the form of a network structure [99]. A recent study reported that astrocytes regulated the establishment of schema memory in rats via the hippocampal CA1-ACC circuit [100]. These authors used a behavioral paradigm of food location pairing (PAs) to dynamically record Ca2+ signals in the CA1-ACC projection neurons and ACC neurons during the formation of schema memory. This strategy revealed the influence of chemical activation in the CA1 astrocyte-Gi pathway on the CA1-ACC network at three stages during the formation of schema memory. Analysis showed that the activation of astrocytes in the CA1 before training led to a failure to form an effective schema memory. In addition, new information relating to Pas could not be absorbed quickly. The imaging of Ca2+ signaling by fiber optic recordings showed that activation of the Gi pathway in CA1 astrocytes reduced the expression of c-FOS transmitted from CA1 to ACC neurons at the beginning and consolidation stages of task learning. Furthermore, during the consolidation stage, this process also reduced the activity of ACC neurons downstream, thus interfering with the establishment of schema memory. When schema memory has been fully established, activation of the Gi pathway in astrocytes no longer affects the activity of ACC neurons [100]. In another study, Lei et al. showed that the chemical activation of astrocytes in the basolateral amygdala participated in the formation of fear memory by regulating communication between the amygdala and the prefrontal cortex [101]. Furthermore, these authors found that the Gq-induced activation of astrocytes during fear learning increased the expression of c-FOS in the basolateral amygdala (BLA) and the mPFC during the fear-conditioned reflex. In addition, retroviral tracking results showed the activation of astrocytes by Gq-induced projection specificity in BLA-mPFC neurons during fear learning. Moreover, electrophysiology recording demonstrated that the activation of Gq signals in astrocytes in the BLA could promote the connection of field potential and phase locking value between the BLA and the mPFC (Fig. 3) [101].

5 THE FUNCTIONAL ROLE OF ASTROCYTES IN MEMORY

5.1 Spatial Memory

In a previous study, Goshen et al. used a two-photon microscope to image the activity of astrocytes in the hippocampal CA1 and found that astrocytes could encode position-related information in the spatial environment [102]. In a familiar environment, astrocytes exhibited continuous enhancement activity in response to reward, but not in the new environment. After learning a new environment or receiving a new reward in a specific environment, the Ca2+ activity of astrocytes increases. These researchers also built a linear regression decoder for each mouse and found that it was possible to predict the position of mice in a familiar environment based on the activity of astrocytes [102]. In addition, Curreli et al. conducted two-photon calcium imaging in astrocytes in the hippocampi of mice that navigated in a virtual space and found that the Ca2+ signaling of astrocytes in the hippocampus encoded spatial information. In addition, the spatial information encoded by astrocytes was complementary and synergistic with the spatial information carried by neurons. The combination of astrocytic and neuronal signals produced further information relating to an animal’s position [103]. This hippocampal functional model assumed that information relating to external environmental variables is crucial for spatial navigation and memory and was encoded only within the neuronal population [104, 105]. These results challenged the established viewpoint, indicating that there may be novel and unexpected cellular mechanisms involved in how brain circuits encode information.

The activation of Gi or Gq GPCR signals via hM4Di and hM3Dq DREADDs or Gq-coupled melanopsin is commonly used to stimulate Ca2+ dynamics in astrocytes. For example, after specifically inhibiting Gq GPCR signals in astrocytes, researchers found that the spatial working memory of experimental mice was damaged [106]. Gene knockout techniques and pharmacological studies have also proved that astrocytes participate in the regulation of spatial memory. For example, connexin 30 (Cx30) and connexin 43 (Cx43) mediate the coupling of astrocytes to form a large intercellular network [107]. The double knockout of Cx30 and Cx43 in astrocytes destroyed the coupling between astrocytes and led to the extensive activation of both astrocytes and microglia. Furthermore, the excitability, excitatory synapse transmission, and LTP of hippocampal CA1 neurons were also affected in these transgenic mice. In addition, the mice exhibited sensory motor defects and a complete lack of spatial learning and memory [108]. In addition, inhibiting the Cx43 half channel (Cx43hc) in the prefrontal cortex was also shown to damage the spatial working memory of experimental rats [109]. Lipopolys-stimulated lipoprotein receptor (LSR) is one of the lipoprotein receptors in the CNS and plays an important role in maintaining cholesterol homeostasis in the brain [110]. In a previous study, El Hajj et al. established a Glast Cre lsrfl/fl conditional KO mouse model to trigger the specific loss of LSR in astrocytes and then assessed the spatial working memory of these mice. These authors found that the spatial working memory was damaged in mice possessing astrocytes in which the LSR had been conditionally knocked out [111]. Mitochondrial superoxide dismutase (SOD2) is an antioxidant that is present in the mitochondrial matrix and can detoxify superoxide production during mitochondrial respiration and maintain mitochondrial homeostasis. The specific reduction of SOD2 in astrocytes caused damage to the hippocampus-dependent spatial working memory of male mice but did not affect the learning and memory of female mice [112]. The GDI1 gene encodes αGDI, a protein that controls the small GTPase cycle and is thought to be involved in vesicular transport. Mutations in the human GDI1 gene have been shown to lead to intellectual impairment [113, 114]. The knockout of GDI1 in mouse astrocytes was previously shown to impair spatial working memory [115]. As a factor secreted by astrocytes, IL-33 is known to play an important role in the synaptic steady-state plasticity of the adult hippocampus. IL-33 promotes the formation of hippocampal excitatory synapses and neuronal transmission in both in vitro hippocampal cultures and in adult mice in vivo; blocking the signal transduction of IL-33 inhibited the steady-state synaptic plasticity of CA1 pyramidal neurons and caused damage to the formation of spatial memory (Table 1) [82].

5.2 Aversive Memory

Astrocytes are also involved in the formation of fear memory. For example, the chemical, genetic or optogenetic Gq activation of hippocampal CA1 astrocytes during memory acquisition in mice was shown to promote the formation of contextual fear memory [116]. In the process of fear memory consolidation, the optogenetics activation of hippocampal astrocytes can reduce fear memory and improve anxiety-like behaviors [117]. Similarly, Gq activation in astrocytes of the medial central amygdala was shown to lead to the disappearance of fear memory in the fear-conditioned reflex paradigm [92]. The chemogenetic activation of astrocytes in the BLA can promote the formation of cued fear memory [101]. These contradictory results indicate that astrocytes in different regions of the brain, or in the same region, might play different roles in different processes of learning, and memory. The normal activity of Rac1 in astrocytes is necessary for the activation of neurons and the formation of memory. The activation and inactivation of Rac1 activity in astrocytes of the BLA has been shown to reduce the excitability of neurons, thus impairing the acquisition of fear memory [118]. In addition, the expression of the cholinergic muscarine 1 receptor (Chrm1) in astrocytes of the hippocampal DG region can regulate the formation of contextual fear memory. The knockout of Chrm1 in astrocytes leads to the impairment of contextual fear memory in mice; furthermore, the overexpression of Chrm1 was shown to rescue the impairment of contextual fear memory in mice [119]. A recent study used electron microscopy to investigate changes in the synaptic coverage of hippocampal astrocytes during encoding and the consolidation of fear memory in mice. These authors found that the encoding and consolidation of contextual fear memory was accompanied by the transient contraction of astrocyte lobules from the synaptic gap and the increased activation of NMDA receptors [120]. In the auditory cortex, fear stimulation activates α7-nicotinic acetylcholine receptors (nAChRs) in the subpopulation of astrocytes in the auditory cortex; knocking out these α7-nAChRs significantly impels the persistence of fear memory [121]. The authors of this study suggested that astrocytes are not only involved in the dynamic regulation of neuronal responses but also play a key role in the long-term storage of information in the brain.

Stress can cause the release of glucocorticoids (GCs), which regulate energy metabolism and play a role in emotional memory. Astrocytes express glucocorticoid receptors (GRs); the selective knockout of GRs in astrocytes impaired the expression of aversive memory in two paradigms of Pavlov’s conditioned reflex: the contextual fear-conditioned reflex and conditioned aversion [122]. Pain is a conscious subjective experience, usually caused by pain stimuli, involving both sensory and emotional factors. Iqbal et al. previously reported that astrocytes in the ACC regulated the visceral pain aversion memory of rats via L-lactic acid signaling [123]. These authors reported that when pain aversion memory was formed in rats, a large amount of L-lactic acid was released from ACC. In contrast, blocking glycogen decomposition in the astrocytes of the ACC reduced the levels of L-lactic acid and destroyed the formation of aversion memory. The injection of exogenous L-lactic acid reversibly transformed the pain aversion memory disorder in experimental rats. In addition, the optogenetic activation of astrocytes in the ACC promoted the release of L-lactic acid and enhanced the formation of pain-related aversion memory. However, short-term activation of the Gi pathway in astrocytes of the ACC prior to conditioned place avoidance training reduced the level of lactate and inhibited pain-related aversion memory [123]. Norepinephrine signaling in astrocytes of the ACC has been reported to play a role in the formation of pain-related aversion memory in rats [124]. The authors of this study reported that actinogenesis activated β2ARs receptors on the astrocytes in the ACC to promote aversive memory and induce learning-dependent plasticity. The specific knockout of β2ARs was shown to inhibit aversive learning and memory. The Gi-induced activation of astrocytes was shown to destroy the aversive memory induced by optogenetic activation of neurons in the locus coeruleus (LC) projecting into the ACC [124].

5.3 Recognition Memory

Recognition memory, the ability to retain and recognize stimuli or events, is the foundation of daily life and survival. In a previous study, Cheung et al. reported the development of a fluorescent probe that can track glutamine in living cells. By using this probe on slices of mouse hippocampi, these authors found that the Cx43hc of astrocytes mediated the activity-dependent transfer of glutamine from astrocytes to synapses. By performing new object recognition experiments, the authors found that inhibiting the function of the Cx43hc led to the impairment of recognition memory in experimental mice. However, mice administered with glutamine did not exhibit memory impairment. This study showed that the formation of new recognition memory in adult mice requires glutamine mobilization in astrocytes [125]. The barrel cortex, as a major component of the surface sensory cortex, has a one-to-one correspondence between each functional column in its fourth layer and the facial antennae of rodents. The neurons in each functional column mainly receive incoming information from the corresponding main antennae and produce evoked responses. In a previous study, Noriega-Preto et al. found that the loss of specific IGF-IR in barrel cortical astrocytes resulted in impairment in the recognition task [71]. In another study, Robin et al. reported that the loss of the CB1 receptor in astrocytes led to the impairment of recognition memory in GFAP-CB1-KO mice. Furthermore, the impairment of recognition memory in GFAP-CB1-KO mice was improved by the exogenous supplementation of D-serine or blocking D-serine catabolism with drugs [60]. Bmal1 is a transcription activator and is considered as the main driving factor of the mammalian biological clock [126]. A previous study found that deletion of the core clock gene Bmal1 in astrocytes led to the destruction of short-term recognition and spatial memory, while pharmacological regulation of the GABA receptor signaling pathway could completely reverse this behavioral defect [127].

6 THE ROLE OF ASTROCYTES IN MEMORY-RELATED DISEASES

AD is characterized by memory impairment and the presence of reactive astrocytes surrounding the amyloid plaques [128]. However, a key question is whether these reactive astrocytes can cause memory impairment. Aging is a recognized risk factor for most neurodegenerative diseases. In addition to neurons, astrocytes also play an important role in the process of brain aging [129]. The main symptoms of PTSD include pathological fear memory enhancement, which manifests as the recurrence or flashback of traumatic memory and avoidance. Neurons, as well as glial cells, are known to be involved in the regulation of the stress response [130]. Chronic traumatic stress can also cause structural atrophy of astrocytes [131]. Although neuronal abnormalities are considered to be the main cause of memory disorders, astrocytes undoubtedly also play a critical role in this pathological process, either by regulating neurons or by self-regulation. Next, we discuss the critical roles of astrocytes in memory-related disorders.

6.1 AD

Previous research showed that reactive astrocytes produced the inhibitory transmitter GABA in a manner that was dependent on monoamine oxidase B (MAO-B). The authors found that the GABA released from astrocytes activated neuronal GABAA and GABAB receptors, thereby inhibiting synaptic transmission and impairing synaptic plasticity and memory [132]. In addition, the excessive production of hydrogen peroxide by severely reactive astrocytes was shown to trigger neurodegeneration in APP/PS1 mice [133]. This finding provided profound insight into the current theory for the pathogenesis of AD. In patients with severe AD, immune therapy against the β-amyloid protein (Aβ) did not delay neurodegeneration and cognitive decline, further emphasizing the pathological role of reactive astrocytes [133].

Astrocytes are known to release GFAP upon activation. Plasma GFAP is an early marker of amyloid protein in AD. By assessing the relationship between GFAP and amyloid protein in the body, researchers discovered that the plasma concentrations of GFAP in the positive group of patients were significantly higher than patients in the amyloid pathology group [134]. In addition, when investigating the correlation between blood GFAP and memory in AD patients, researchers found that higher GFAP levels were associated with lower memory scores; consequently, an increase in GFAP, a marker of astrocyte activation, may reflect a decline in memory function [135].

The accumulation of Aβ and phosphorylated tau are common pathological features of AD. High levels of aquaporin-4 (AQP4) in astrocytes are known to facilitate the clearance of soluble Aβ from the brain parenchyma along the paravascular pathway [136]. In contrast, the knockout of AQP4 enhanced the production of Aβ in the brains of APP/PS1 mice [137]. In another study, Du et al. found that the downregulation of hippocampal GluN2A in astrocytes could aggravate Aβ-induced spatial memory impairment [138]. Astrocytes possess a unique non-circulating metabolic pathway for urea. Upon commencing Aβ treatment, astrocytes begin to cycle urea, thus eliciting an increase in the levels of aspartic acid and putrescine; these can induce the impairment of memory [139]. Importantly, tau was found to accumulate in astrocytes of the hippocampal DG region in AD patients [140]. In a mouse model, the overexpression of tau in astrocytes can lead to alterations in mitochondrial dynamics and functionality, thereby inducing neuronal dysfunction and memory deficits [140].

Lipid imbalance is an important feature of several neurodegenerative diseases, especially in AD. APOE4 is a known risk gene for AD [141]; a previous study reported that astrocytes are the major cell type that produces the most APOE [142]. APOE4 can cause degenerative changes in the pericytes of capillaries in the brain, thereby accelerating the destruction of the blood-brain barrier (BBB). Impairment of the BBB makes it easier for toxic substances in the blood to enter the brain, thus leading to the cognitive decline of APOE4 carriers [143]. In addition, APOE4, rather than APOE3, can activate the CypA-MMP9 pathway in cerebrospinal fluid, thus accelerating the breakdown of the BBB and leading to neuronal and synaptic dysfunction [143]. In addition, APOE4 was shown to destroy the lipid homeostasis of astrocytes derived from human induced pluripotent stem cells (iPSC). Human astrocytes with the APOE4 genotype are known to contain a large number of neutral lipids and cholesterol; these astrocytes can accumulate a large number of lipid droplets, in which unsaturated fat acid chains can lead to an imbalance in the lipid status of astrocytes [144]. Gliican-4 (GPC-4) is a protein secreted by astrocytes and regarded as the binding partner of APOE4 to drive the hyperphosphorylation of tau [145]. In addition, researchers recently discovered that human-specific APOE4 drove disorders of lipid metabolism in astrocytes and microglia, thus increasing the risk of AD [146]. In addition, the selective removal of APOE4 from astrocytes was shown to reduce Tau-mediated neurodegeneration [147].

Based on basic experimental evidence, targeting astrocytes might improve the memory impairment of AD (Fig. 4). For example, the oral application of L-serine was shown to prevent the synaptic and spatial memory impairment of a mouse model of AD [148]. L-serine, the precursor of D-serine, is produced by glycolysis in the astrocytes. The impaired synthesis of L-serine is known to aggravate the cognitive impairment of AD. Moreover, AD mice were shown to exhibit a low level of occupancy in co-agonist sites for NMDAR. The oral application of L-serine was shown to improve the impairment of synaptic function and spatial memory in AD mice [148]. APOE4 is one of the strongest genetic risk factors for late-onset AD [145]. In a previous study, Sienski et al. found that the additional supplementation of choline, a dietary supplement that is safe for human beings, could reverse the damage caused by APOE4 in astrocytes [144]. A recent study found that ornithine decarboxylase 1 (ODC1) plays a key role in separating the detoxicated urea cycle and the degradation pathway for putrescine, a toxic by-product. Silencing ODC1 in astrocytes promotes the transformation of ornithine to putrescine and reduces the production of putrescine and GABA in a mouse model of AD, thus reducing memory impairment in AD patients [139]. Previous research found that the Aβ-dependent transient receptor potential A1 (TRPA1) calcium channel could trigger the excessive activity of hippocampal astrocytes and then induce the excessive activity of nearby neurons [149]. In this regard, a recent study found that the blockade of the TRPA1 calcium channel could normalize the activity of astrocytes, help to maintain the integrity of synaptic structure and improve spatial working memory in a mouse model of AD [150]. In addition, the overexpression of the astrocytic Ca2+ sensor STIM1 was shown to rescue LTP impairment in female mice with AD [151]; in addition, astrocytes were shown to exhibit impaired Ca2+ activity in PS2/APP mouse models of AD. This low level of Ca2+ activity was associated with the reduced storage of Ca2+ and the downregulation of STIM1. Moreover, reduced Ca2+ activity in astrocytes has been shown to lead to long-term impaired synaptic plasticity in PS2APP mice. In addition to improving impaired tactile recognition memory, the overexpression of STIM1 in astrocytes also rescued Ca2+ activity in astrocytes and synaptic plasticity [151]. The overactivity of astrocytes is an important factor in the abnormal functionality of neural networks in AD. Research showed that long-term treatment with a P2Y1 purine receptor (P2Y1R) antagonist reduced reactivity in astrocytes and normalized astrocytic dysfunction and neural networks, thus improving network dysfunction and spatial memory impairment in a model of AD [152].

A pertinent question at this point is whether astrocytes are able to clear the accumulation of β-amyloid protein and tau protein to improve the symptoms of AD. A recent study found that the combination of gemfibrozil (GFB) and retinoic acid (RA), a drug used to treat high cholesterol, could activate PPARα and then enhance the effect of astrocytes on Aβ absorption and the degradation of amyloid protein, thus reducing brain Aβ burden, improving spatial learning, and memory in the 5 x FAD mouse model of AD [153]. Furthermore, a recent study showed that the programming of microglia with astrocyte-derived interleukin-3 (IL-3) improved pathological effects and cognitive function in AD [154]. These researchers found that IL-3 was mainly derived from a subpopulation of astrocytes in the mouse brain and that Il3−/−5xFAD mice suffered from short-term and spatial memory impairment following IL-3 knockout. As AD progresses, microglia increase their sensitivity to IL-3 by expressing IL-3Rα; the IL-3 induces extensive programming of the microglia transcriptome, deploys immune and motor responses, and promotes microglial immune activation, and the aggregation and clearance of Aβ and tau aggregates [154]. During the development of AD, astrocytes exhibit extensive changes at the transcription and protein levels. This generates the question as to whether the symptoms of AD could be improved by targeting specific key transcription factors. Jiwaji et al. showed that the overexpression of Nrf2, an astrocyte-specific transcription factor, reduced the accumulation of Aß-deposition and phosphorylated tau and rescued transcriptional disorders in the brain and the damage caused to fear memory [155].

6.2 Brain Aging

The morphology and functionality of astrocytes are known to change remarkably in aging mice; this is manifested by the gradual atrophy of morphology, the significant reduction of astrocyte-astrocyte coupling, the deficiency of K+ clearance and glutamate recovery, and the spatiotemporal reorganization of Ca2+ events [156, 157]. In addition, aging can change the spontaneous Ca2+ activity of astrocytes in the subcellular domain. Further evidence suggests that the reduction of Ca2+ activity in the endfeet of astrocyte is related to a reduction in AQP4 expression [158].

In fact, aging may have a profound impact on the functionality of astrocytes. For example, the expression patterns of specific genes in astrocytes were shown to change with age, while the patterns of gene expression in neurons were only mildly affected [159]. In addition, the astrocytes of aged mice are known to exhibit A1-like reactivity, while A1-type astrocytes were demonstrated to lose normal functionality when compared with normal astrocytes, such as the production of complement components and strong neurotoxicity [160, 161]. Other research showed that senile astrocytes accumulated in the brain and showed reduced functionality and the secretion of senescence-associated secretory phenotype factors, which are known to contribute to neuroinflammation and neurotoxicity [162, 163]. By analyzing the transcriptome of astrocytes in aged mice, researchers demonstrated that the genes that are upregulated in astrocytes are related to the immune signaling pathway and synaptic elimination [164, 165]. Excitatory amino acid transporter 2 (EAAT2) is the main glutamate transporter in the brain and is predominantly expressed in astrocytes [166]. Sharma et al. further showed that the lack of EAAT2 in astrocytes rather than neurons in the hippocampus concurred with the gene expression profiles associated with human aging and AD. In addition, the lack of EAAT2 in astrocytes is known to accelerate age-related cognitive deficits [167].

The functionality of astrocytes in old animals is known to be abnormal. This suggests that it may be possible to reverse the aging process in the brain by transplanting young and healthy astrocytes. Yang et al. found that the transplantation of glial progenitor cells derived astrocytes into the cerebral cortex of adult mice improved the microenvironment of the brain in aging mice, promoted neuronal survival, and restored memory [168]. In another study, Xu et al. found that Yes-associated Protein (YAP) prevented the premature aging of astrocytes and the cognitive decline of Alzheimer's disease by regulating the cyclin-dependent kinase 6 (CDK6) signaling pathway [169]. These authors found that YAP was down-regulated and inactivated in a Hippo pathway-dependent manner in the hippocampal astrocytes of aging mice and a mouse model of AD, as well as in aging astrocytes induced by D-galactose and paraquat. The conditional knockout of YAP in astrocytes was shown to promote the aging of astrocytes, both in vivo and in vitro. Furthermore, the heterotopic overexpression of CDK6 was shown to prevent the aging of astrocytes caused by YAP knockout, at least in part. In addition, previous research showed that YAP signaling was activated by Xmup-1, an inhibitor of Hippo kinase MST1/2 and that the aging of astrocytes was delayed in vivo, thereby improving the cognitive function of elderly mice and mice with AD [169].

Research has also shown that the levels of miR-335-3p were increased in aged astrocytes in culture and in aged hippocampi. The impairment of cholesterol synthesis in astrocytes caused by the overexpression of miR-335-3p down-regulated the synaptic protein PSD95 in neurons while reducing the levels of miR-335-3p in the aged mouse hippocampus increased the levels of PSD95 protein and the production of cholesterol [170]. Copper blue protein (CP) is an iron oxide enzyme that plays a crucial role in maintaining iron homeostasis [171]. Li et al. demonstrated that the knockout of CP in astrocytes reduced age-dependent iron accumulation in the brain and improved the learning, and memory functions of elderly mice [172].

6.3 PTSD

Previous research showed that chronic restraint or traumatic stress can cause damage to hippocampal glia, especially astrocytes and that these events are related to emotional and cognitive impairment [173-176]. In addition, by utilizing the stress-enhanced fear learning (SEFL) model, researchers found that the stress-induced IL-1 signal in the dorsal hippocampus, which is crucial for the development of SEFL, and astrocytes were the main source of IL-1 production [12]. Hippocampal atrophy or impaired hippocampal function is one of the most common morphological changes reported in PTSD patients [177, 178]. In an animal model of PTSD, hippocampal atrophy is caused by the loss of astrocytes, at least in part [175, 179]. A recent proteome-wide association study of PTSD revealed that 11 genes were involved in the pathogenesis of PTSD, several of which were preferentially expressed not only in neurons but also in astrocytes and other glial cells [180].

The extinction of fear memory is an important therapeutic target for PTSD [181-183]. Previous research showed that cotinine promoted the extinction of fear memory in rodents and that the infusion of cotinine into the medial prefrontal cortex increased the survival of astrocytes [179, 184]. Kir4.1 is an inward rectifying K+ channel expressed only in glial cells and is considered a potential therapeutic target for mental disorders [185, 186]. In lipopolysaccharide (LPS) or single prolonged stress (SPS) mouse models, the expression levels of Kir4.1 in hippocampal astrocytes were significantly increased, while the reduction of Kir4.1 in the hippocampus promoted the extinction of fear [187]. Fibroblast growth factor 2 (FGF2) is a multifunctional growth factor that is essential for the development of the CNS [188]. Research has shown that intraperitoneal injection of FGF2 can block the SPS-induced PTSD fear response and anxiety behavior via astrocytic but not neuronal mechanisms [189]. Further analysis revealed that FGF2 restored glutamate uptake in astrocytes via the JAK/STAT pathway and improved fear and anxiety-like behavior in a rat model of PTSD [190].

6.4 Addiction

Astrocytes are believed to be involved in the development of drug addiction [191-193]. Cannabis-induced memory impairment is also known to correlate with the functionality of astrocytes. Delta-9 tetrahydrocannabinol (THC), a component of cannabis, is considered to be a partial agonist of cannabinoid receptor 1 in the brain. Acute exposure to THC is known to cause damage to working memory [66]. Hippocampal astrocytes express endogenous schizophrenia dominant negative disruption protein 1 (DN-DISC1), and exposure to THC during puberty was shown to synergistically affect the recognition and memory of adult mice [194]. Cocaine-related memory is an important source of desire, and interferes with drug withdrawal ability. Reducing the intensity of clue drug memory by extinction is of therapeutic value for the treatment of cocaine addiction. In a previous study, Shelkar et al. found that the selective ablation of the GluN1 subunit in astrocytes of the nucleus accumbens promoted the extinction of cocaine reward memory [195]. In addition, destroying the production of lactic acid by astrocytes temporarily impaired the preference for cocaine [196]. Methamphetamine (METH) is a common substance of abuse. Recent research demonstrated that METH withdrawal caused damage to the spatial memory of mice and led to an increase in glutamate levels in the hippocampal CA. Following METH withdrawal, astrocytes exhibited impaired glutamate clearance ability, as demonstrated by the increased expression of transcription activating factor 3 (p-STAT3) in astrocytes. By selectively knocking down STAT3, astrocytes in the hippocampal CA1 were able to recover their ability to clear glutamate and improve the damage to spatial memory caused by METH withdrawal in experimental mice [197].

7 FUTURE PROSPECTS

Astrocytes are considered to be a homogenous cell population, and it is generally assumed that astrocytes from different brain regions are functionally interchangeable. However, recent studies have proven that astrocytes, like neurons, are heterogeneous. Astrocytes are distributed in various brain regions, exhibit regional specificity and can distinguish between different neuronal subtypes and regulate their activities [1, 10, 198]. Astrocytes have different effects on neurons according to their genetic characteristics. For example, Huang et al. used the recently developed Aldh1l1-CreER mouse and specifically knocked out the NFIA transcription factor. Then, the authors analyzed changes in four brain regions, including the olfactory bulb, cortex, hippocampus and brain stem, to identify changes in the morphological, physiological and gene expression characteristics of astrocytes. Surprisingly, astrocytes in the hippocampus showed significant changes but not the other three regions. Astrocytes in the hippocampus exhibited lower levels of calcium activity, a weaker ability to detect neurotransmitters, and reduced tightness in the connections with neurons. All of these changes in morphology and function were related to learning and memory [53]. Chrdl1 is highly enriched in cortical astrocytes and is known to regulate synaptic function [199]. Although significant progress has been made, there are still many challenges that need to be resolved. For example, we are lacking specific techniques to better understand the intrinsic characteristics of astrocytes. Moreover, the local circuits and behavioral specificity of neurons and the astrocytes that interact with neurons still need to be clarified. This requires the development of better astrocyte-specific research tools, technologies and experimental designs to resolve the remaining challenges and bridge the gaps in our existing knowledge.

A deeper understanding of the brain will stimulate new types of biological computing and artificial intelligence. For example, a recent study selected two spiking neural networks, cortical spiking networks (CSNs) and cortical neuron-astrocyte networks (CNANs), to investigate these brain-inspired networks from a learning perspective and found that CNANs provided more powerful information encoding functions than CSNs [118]. Furthermore, the transfer of information from the CNANs to the CSNs could improve the recognition ability of CSNs without relying on a time-consuming training process [200]. Moreover, computational models also provide evidence and understanding of the role of astrocytes in the processing of memory in the brain. Recently, researchers proposed a neuron-glia network model and used this model to demonstrate that interactions between synapses and astrocytes can produce various forms of working memory [201]. In addition, a synaptic attractor model of working memory has also been developed and used to investigate the role of astrocytes in the regulation of working memory [202]. These authors found that astrocytes were key determinants for the duration of working memory in this model and that astrocyte signals can promote top-down volitional control of different mechanisms of working memory representation and duration [202].

With the development of viral vector technologies such as adeno-associated viruses (AAVs) and retroviruses, rapid progress has been made in the field of cell reprogramming [203]. Moreover, research has proved that astrocytes have the potential to be reprogrammed. For example, Xiang et al. showed that overexpression of the NeuroD1 gene via an AAV vector could transform astrocytes in the brain into neurons [204]. In addition, Zhang et al. demonstrated that overexpression of transcription factor DLX2 could transform mature astrocytes in the brains of mice into induced neural progenitor cells, which subsequently differentiated further into neurons, astrocytes and oligodendrocytes [205]. In another study, a retrovirus was used to overexpress the NeuroD1 transcription factor in the cortex of a mouse model of AD; this study clearly demonstrated that astrocytes could be reprogrammed into glutamate neurons, which were subsequently integrated into local neural circuits [206]. However, it remains unclear as to whether the reprogramming of glial cells into neurons can rescue cognitive deficits in AD mouse models.

Astrocytes not only influence synaptic plasticity in neurons; they also regulate neural circuits. Importantly, astrocytes may also represent a potential therapeutic target for memory-related neurological diseases. Our understanding of the involvement of astrocytes in memory is still incomplete, and more research is needed to confirm existing findings and better elucidate the specific role played by astrocytes in memory processes. For example, there are still many memory-related astrocyte activities that are not fully understood during the acquisition and storage of information. This is because it is difficult to identify well-defined astrocytes in vivo and monitor their activity in animal models during different learning stages and different learning tasks over several days. Moreover, the diversity of signal pathways by which astrocytes influence neuronal signaling, the many dimensions of memory, as well as the diversity of memory mechanisms all represent major challenges if we are to gain a comprehensive understanding of the function of astrocytes in memory. In addition, although recent evidence suggests that astrocytes may serve as a pathogenic and treatment target for memory disorders, this needs to be confirmed in future research involving specific manipulation by genetic methods.

CONCLUSION

In conclusion, this review provides important reference guidelines relating to our current understanding of memory and memory-related disorders from the perspective of astrocytes. Targeting astrocytes might represent a potential strategy with which to treat memory-related neurological diseases.

ACKNOWLEDGEMENTS

Declared none.

AUTHORS’ CONTRIBUTIONS

JW and GQZ designed the review. JW, PC, YQ and GQZ completed the writing of this paper.

LIST OF ABBREVIATIONS

A1Rs Adenosine Type 1 Receptor

AD Alzheimer’s Disease

BDNF Brain-derived Neurotrophic Factor

CB1R Cannabinoid Receptor Type 1

Cx30 Connexin 30

GABA γ-aminobutyric Acid

GPCR G protein-coupled Receptors

IL-33 Interleukin-33

LTP Long-term Potentiation

PTSD Posttraumatic Stress Disorder

STDP Spike-time Dependent Plasticity

TBS Theta Burst Stimulation

α7nAChR α7-nicotine Acetylcholine Receptor

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

This research was supported by Anhui Natural Science Foundation (grant Nos. 2208085MH282), Key Research and Development Plan of Anhui Province (202104j07020004), Key Project of Anhui Natural Science Research (grant No. 2022AH050462).

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

Fig. (1) Mechanisms involved in the regulation of astrocytes in synaptic plasticity.

Fig. (2) Astrocytes regulate the activity of neural networks. (A) Schematic diagram showing the experimental manipulation of simultaneous recordings of local field potentials (LFP) in the dorsal hippocampus (dHIP, blue) and medial prefrontal cortex (mPFC, orange); (B) Overlap of representative theta-filtered LFP traces in the mPFC and dHIP recorded in WT and dnSNARE and dnSNARE mice, compared to WT mice. dnSNARE mice showed reduced theta synchronization, and the intraperitoneal injection of D-serine restored theta synchronization in the dHIP-mPFC. (C) Schematic diagram showing the experimental manipulation of local field potential (LFP) recordings in the medial prefrontal cortex (mPFC, orange) and melanopsin optogenetics stimulation of astrocytes (blue); (D) Representative low-gamma (30-60 Hz specific frequency band) filtering LFP traces from control and GFAP/PFCΔGb and melanopsin transfected mice during T-maze behavioral processes.

Fig. (3) Astrocytes regulate neural circuits. (A) A subpopulation of pyramidal neurons (blue) in the hippocampal CA1 area projects to the ACC, and hippocampal CA1 area astrocytes (green) regulate the activity of this subpopulation, thus allowing ACC neuronal labeling, a process critical for remote and schema-associated memory. In contrast, the Gi activation of astrocytes (gray) in the hippocampal CA1 area specifically inhibits ACC projections to CA1 neurons during memory formation, resulting in the impaired formation of remote memory. Recent memories may be mediated by CA1 neurons that do not project to the ACC (orange). (B) Gq activation of BLA astrocytes (red) specifically enhances communication between the BLA-MPFC and increases auditory cue fear memories. (C) A subpopulation of LC neurons projecting to the ACC is critical for aversive learning and memory, and the optogenetics activation of LC neurons projecting to the ACC enhances aversive memory formation. However, when astrocytes are activated by Gi (gray), there is a disruption in the optogenetics process of LC neuron recruitment to the ACC, thus inhibiting the enhancement of aversive memory.

Fig. (4) The role of astrocytes in memory-related disorders. (A) Astrocytes exhibit alterations in memory-related disorders in several aspects: morphological structure, the acquisition of a reactive phenotype by astrocytes, dysregulation of calcium homeostasis, alterations in gene expression, and metabolic imbalances. (B) Based on experimental evidence, several strategies, including pharmacological approaches, have been proposed to target astrocytes to improve memory.

Table 1 The roles of astrocytes performed in memory.

Memory
Types	Manipulation or Detection Methods	Proposed Mechanism	Outcomes	References	
Spatial memory	Long-term imaging of hippocampal CA1 astrocyte by two-photon microscopy	Calcium kinetics of astrocyte	Astrocytes participate in encoding spatial memory	[102]	
Simultaneous calcium imaging of hippocampal astrocytes and neurons by two-photon microscopy	Calcium kinetics of astrocyte	The calcium signal of astrocytes encodes spatial information, which is complementary to the spatial information encoded by neurons	[103, 106]	
β-adrenergic receptor kinase 1 specifically inhibits the Gq GPCR signal of astrocyte	Gq GPCR signaling	Impairment of spatial memory	[108]	
Astrocyte-specific Cx30 and Cx43 double knockout	Synaptic transmission and LTP	Impairment of spatial memory	[109]	
Pharmacological blockade of the CX43 half channel in astrocytes in PFC	Synaptic transmission	Impairment of spatial memory	[111]	
Specific Knockout of Lipoprotein Receptor LSR in astrocyte	Cholesterol metabolism	Impairment of spatial and working memory	[112]	
Selective ablation of astrocyte SOD2	Mitochondrial homeostasis, D-serine and LTP	Hippocampus-dependent spatial working memory in male mice	[115]	
Gdi1 gene deletion in astrocyte	Glycometabolism	Impairment of spatial memory	[82]	
Inhibition of IL-33/ST2 signaling in astrocyte	Homeostatic synaptic plasticity	Impairment of spatial memory	[68]	
IP3R2 gene deletion	LTD	Impairment of spatial working memory, fear memory, and recognition memory	[89]	
Expression of dnSNARE in astrocyte	Theta wave synchronization in the hippocampal and prefrontal cortex	Impairment of spatial working memory and recognition memory	[89]	
Light-activated adenylate cyclase increases cAMP levels in astrocytes	LTP	Improvement of spatial memory	[61]	
Overexpression of Piezo1 in astrocyte	LTP	Enhancement of spatial memory	[62]	
Specific deletion of CB1R in hippocampal astrocyte	LTD	Spatial working memory impairment induced by exogenous cannabinoids	[66]	
Aversive memory	Chemical or optogenetics activation of Gq GPCR signals in CA1 astrocyte	LTP	Enhancement of contextual fear memory	[116]	
Chemogenetic activation of Gq GPCR signals in basolateral amygdala (BLA) astrocyte	Amygdala prefrontal cortex communication	Enhancement of cued fear memory	[101]	
Optogenetics activation or inhibition of Rac1
activity in basolateral amygdala astrocytes	Inhibiting neuronal activation (reducing neuronal excitability)	Suppressing fear memory acquisition	[118]	
Chrm1 gene deletion in astrocyte	Hippocampal
neurogenesis	Contextual fear memory impairment	[119]	
Specificity Knocking out α7-nAChR of astrocytes in the auditory cortex	Astrocyte calcium signal	Persistent impairment of fear memory	[121]	
Specific knocking out glucocorticoid receptor (GR) in astrocyte	Glucose metabolism	Contextual fear memory impairment	[122]	
Pharmacological inhibition of glycogen decomposition of astrocyte in anterior cingulate cortex (ACC) and short-term activation of astrocyte in ACC	L-lactic acid	Impaired aversion memory related to pain	[123]	
Optogenetics activation of ACC astrocyte β2ARs
Chemogenesis activates the Gi pathway in
astrocytes and AAV, knocking down astrocyte β2AR	Locus coeruleus (LC) - anterior cingulate cortex ACC neural circuit	Promoting pain-related aversion memory
Inhibiting pain-related aversion memory	[124]	
Recognition memory	Inhibition of Ca2+dependent vesicle release in
astrocyte	Gamma oscillation	Impairment of recognition memory	[87]	
The specific knockout of phagocytic receptor MEGF10 in astrocyte	Astrocyte phagocytosis synapse, LTP, LTD	Impairment of recognition memory	[80]	
The specific knockout of astrocyte CX43	Glutamine transfer	Impairment of recognition memory	[125]	
Specific deletion of IGF-IR in cortical astrocyte	LTP, LTD	Impairment of recognition memory	[71]	
Deletion of CB1 receptor in astrocyte	LTP and D-serine	Impairment of recognition memory	[60]	
Knockout of Bmal1 in astrocyte	GABA signaling	Impairment of recognition memory	[127]
==== Refs
REFERENCES

1 Haim L.B. Rowitch D.H. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 2017 18 1 31 41 10.1038/nrn.2016.159 27904142
2 Chung W.S. Allen N.J. Eroglu C. Astrocytes control synapse formation, function, and elimination. Cold Spring Harb. Perspect. Biol. 2015 7 9 a020370 10.1101/cshperspect.a020370 25663667
3 Araque A. Parpura V. Sanzgiri R.P. Haydon P.G. Tripartite synapses: Glia, the unacknowledged partner. Trends Neurosci. 1999 22 5 208 215 10.1016/S0166-2236(98)01349-6 10322493
4 Khakh B.S. Deneen B. The emerging nature of astrocyte diversity. Annu. Rev. Neurosci. 2019 42 1 187 207 10.1146/annurev-neuro-070918-050443 31283899
5 Verkhratsky A. Nedergaard M. Physiology of astroglia. Physiol. Rev. 2018 98 1 239 389 10.1152/physrev.00042.2016 29351512
6 Akther S. Hirase H. Assessment of astrocytes as a mediator of memory and learning in rodents. Glia 2022 70 8 1484 1505 10.1002/glia.24099 34582594
7 Khaspekov L.G. Frumkina L.E. Molecular mechanisms of astrocyte involvement in synaptogenesis and brain synaptic plasticity. Biochemistry 2023 88 4 502 514 10.1134/S0006297923040065 37080936
8 Dienel G.A. Schousboe A. McKenna M.C. Rothman D.L. A tribute to Leif Hertz: The historical context of his pioneering studies of the roles of astrocytes in brain energy metabolism, neurotransmission, cognitive functions, and pharmacology identifies important, unresolved topics for future studies. J. Neurochem. 2023 15812 10.1111/jnc.15812 36928655
9 Chen Y.H. Jin S.Y. Yang J.M. Gao T.M. The memory orchestra: Contribution of astrocytes. Neurosci. Bull. 2023 39 3 409 424 10.1007/s12264-023-01024-x 36738435
10 Endo F. Kasai A. Soto J.S. Yu X. Qu Z. Hashimoto H. Gradinaru V. Kawaguchi R. Khakh B.S. Molecular basis of astrocyte diversity and morphology across the CNS in health and disease. Science 2022 378 6619 eadc9020 10.1126/science.adc9020 36378959
11 Arranz A.M. De Strooper B. The role of astroglia in Alzheimer’s disease: Pathophysiology and clinical implications. Lancet Neurol. 2019 18 4 406 414 10.1016/S1474-4422(18)30490-3 30795987
12 Jones M.E. Lebonville C.L. Paniccia J.E. Balentine M.E. Reissner K.J. Lysle D.T. Hippocampal interleukin-1 mediates stress-enhanced fear learning: A potential role for astrocyte-derived interleukin-1β. Brain Behav. Immun. 2018 67 355 363 10.1016/j.bbi.2017.09.016 28963000
13 Yang J. Chen J. Liu Y. Chen K.H. Baraban J.M. Qiu Z. Ventral tegmental area astrocytes modulate cocaine reward by tonically releasing GABA. Neuron 2023 111 7 1104 1117.e6 10.1016/j.neuron.2022.12.033 36681074
14 Lee S.H. Mak A. Verheijen M.H.G. Comparative assessment of the effects of DREADDs and endogenously expressed GPCRs in hippocampal astrocytes on synaptic activity and memory. Front. Cell. Neurosci. 2023 17 1159756 10.3389/fncel.2023.1159756 37051110
15 Goshen I. The optogenetic revolution in memory research. Trends Neurosci. 2014 37 9 511 522 10.1016/j.tins.2014.06.002 25022518
16 Yu X. Nagai J. Khakh B.S. Improved tools to study astrocytes. Nat. Rev. Neurosci. 2020 21 3 121 138 10.1038/s41583-020-0264-8 32042146
17 Savtchenko L.P. Bard L. Jensen T.P. Reynolds J.P. Kraev I. Medvedev N. Stewart M.G. Henneberger C. Rusakov D.A. Disentangling astroglial physiology with a realistic cell model in silico. Nat. Commun. 2018 9 1 3554 10.1038/s41467-018-05896-w 30177844
18 Verkhratsky A. Reyes R.C. Parpura V. TRP channels coordinate ion signalling in astroglia. Rev. Physiol. Biochem. Pharmacol. 2014 166 1 22 23784619
19 Semyanov A. Henneberger C. Agarwal A. Making sense of astrocytic calcium signals - from acquisition to interpretation. Nat. Rev. Neurosci. 2020 21 10 551 564 10.1038/s41583-020-0361-8 32873937
20 Agarwal A. Wu P.H. Hughes E.G. Fukaya M. Tischfield M.A. Langseth A.J. Wirtz D. Bergles D.E. Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron 2017 93 3 587 605.e7 10.1016/j.neuron.2016.12.034 28132831
21 Bojarskaite L. Bjørnstad D.M. Pettersen K.H. Cunen C. Hermansen G.H. Åbjørsbråten K.S. Chambers A.R. Sprengel R. Vervaeke K. Tang W. Enger R. Nagelhus E.A. Astrocytic Ca2+ signaling is reduced during sleep and is involved in the regulation of slow wave sleep. Nat. Commun. 2020 11 1 3240 10.1038/s41467-020-17062-2 32632168
22 Wu Y.W. Gordleeva S. Tang X. Shih P.Y. Dembitskaya Y. Semyanov A. Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes. Glia 2019 67 2 246 262 10.1002/glia.23537 30565755
23 Denizot A. Arizono M. Nägerl U.V. Soula H. Berry H. Simulation of calcium signaling in fine astrocytic processes: Effect of spatial properties on spontaneous activity. PLOS Comput. Biol. 2019 15 8 e1006795 10.1371/journal.pcbi.1006795 31425510
24 Lines J. Martin E.D. Kofuji P. Aguilar J. Araque A. Astrocytes modulate sensory-evoked neuronal network activity. Nat. Commun. 2020 11 1 3689 10.1038/s41467-020-17536-3 32704144
25 Boddum K. Jensen T.P. Magloire V. Kristiansen U. Rusakov D.A. Pavlov I. Walker M.C. Astrocytic GABA transporter activity modulates excitatory neurotransmission. Nat. Commun. 2016 7 1 13572 10.1038/ncomms13572 27886179
26 Kofuji P. Araque A. G-protein-coupled receptors in astrocyte-neuron communication. Neuroscience 2021 456 71 84 10.1016/j.neuroscience.2020.03.025 32224231
27 Bazargani N. Attwell D. Astrocyte calcium signaling: The third wave. Nat. Neurosci. 2016 19 2 182 189 10.1038/nn.4201 26814587
28 Volterra A. Liaudet N. Savtchouk I. Astrocyte Ca2+ signalling: An unexpected complexity. Nat. Rev. Neurosci. 2014 15 5 327 335 10.1038/nrn3725 24739787
29 Srinivasan R. Huang B.S. Venugopal S. Johnston A.D. Chai H. Zeng H. Golshani P. Khakh B.S. Ca2+ signaling in astrocytes from Ip3r2−/− mice in brain slices and during startle responses in vivo. Nat. Neurosci. 2015 18 5 708 717 10.1038/nn.4001 25894291
30 Semyanov A. Spatiotemporal pattern of calcium activity in astrocytic network. Cell Calcium 2019 78 15 25 10.1016/j.ceca.2018.12.007 30579813
31 Arizono M. Inavalli V.V.G.K. Panatier A. Pfeiffer T. Angibaud J. Levet F. Ter Veer M.J.T. Stobart J. Bellocchio L. Mikoshiba K. Marsicano G. Weber B. Oliet S.H.R. Nägerl U.V. Structural basis of astrocytic Ca2+ signals at tripartite synapses. Nat. Commun. 2020 11 1 1906 10.1038/s41467-020-15648-4 32312988
32 Georgiou L. Echeverría A. Georgiou A. Kuhn B. Ca 2+ activity maps of astrocytes tagged by axoastrocytic AAV transfer. Sci. Adv. 2022 8 6 eabe5371 10.1126/sciadv.abe5371 35138891
33 Stobart J.L. Ferrari K.D. Barrett M.J.P. Glück C. Stobart M.J. Zuend M. Weber B. Cortical circuit activity evokes rapid astrocyte calcium signals on a similar timescale to neurons. Neuron 2018 98 4 726 735.e4 10.1016/j.neuron.2018.03.050 29706581
34 Wang Y. DelRosso N.V. Vaidyanathan T.V. Cahill M.K. Reitman M.E. Pittolo S. Mi X. Yu G. Poskanzer K.E. Accurate quantification of astrocyte and neurotransmitter fluorescence dynamics for single-cell and population-level physiology. Nat. Neurosci. 2019 22 11 1936 1944 10.1038/s41593-019-0492-2 31570865
35 Zhu G. Liu Y. Wang Y. Bi X. Baudry M. Different patterns of electrical activity lead to long-term potentiation by activating different intracellular pathways. J. Neurosci. 2015 35 2 621 633 10.1523/JNEUROSCI.2193-14.2015 25589756
36 Zhu G. Briz V. Seinfeld J. Liu Y. Bi X. Baudry M. Calpain-1 deletion impairs mGluR-dependent LTD and fear memory extinction. Sci. Rep. 2017 7 1 42788 10.1038/srep42788 28202907
37 Frankland P.W. Bontempi B. The organization of recent and remote memories. Nat. Rev. Neurosci. 2005 6 2 119 130 10.1038/nrn1607 15685217
38 Magee J.C. Grienberger C. Synaptic plasticity forms and functions. Annu. Rev. Neurosci. 2020 43 1 95 117 10.1146/annurev-neuro-090919-022842 32075520
39 Allen N.J. Lyons D.A. Glia as architects of central nervous system formation and function. Science 2018 362 6411 181 185 10.1126/science.aat0473 30309945
40 Bliss T.V.P. Lømo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 1973 232 2 331 356 10.1113/jphysiol.1973.sp010273 4727084
41 Malenka R.C. Bear M.F. LTP and LTD: An embarrassment of riches. Neuron 2004 44 1 5 21 10.1016/j.neuron.2004.09.012 15450156
42 Nguyen P.V. Abel T. Kandel E.R. Requirement of a critical period of transcription for induction of a late phase of LTP. Science 1994 265 5175 1104 1107 10.1126/science.8066450 8066450
43 Sherwood M.W. Arizono M. Hisatsune C. Bannai H. Ebisui E. Sherwood J.L. Panatier A. Oliet S.H.R. Mikoshiba K. Astrocytic IP3Rs: Contribution to Ca2+ signalling and hippocampal LTP. Glia 2017 65 3 502 513 10.1002/glia.23107 28063222
44 Navarrete M. Perea G. de Sevilla D.F. Gómez-Gonzalo M. Núñez A. Martín E.D. Araque A. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity. PLoS Biol. 2012 10 2 e1001259 10.1371/journal.pbio.1001259 22347811
45 Liu J.H. Zhang M. Wang Q. Wu D.Y. Jie W. Hu N.Y. Lan J.Z. Zeng K. Li S.J. Li X.W. Yang J.M. Gao T.M. Distinct roles of astroglia and neurons in synaptic plasticity and memory. Mol. Psychiatry 2022 27 2 873 885 10.1038/s41380-021-01332-6 34642458
46 Requie L.M. Gómez-Gonzalo M. Speggiorin M. Managò F. Melone M. Congiu M. Chiavegato A. Lia A. Zonta M. Losi G. Henriques V.J. Pugliese A. Pacinelli G. Marsicano G. Papaleo F. Muntoni A.L. Conti F. Carmignoto G. Astrocytes mediate long-lasting synaptic regulation of ventral tegmental area dopamine neurons. Nat. Neurosci. 2022 25 12 1639 1650 10.1038/s41593-022-01193-4 36396976
47 Henneberger C. Papouin T. Oliet S.H.R. Rusakov D.A. Long-term potentiation depends on release of d-serine from astrocytes. Nature 2010 463 7278 232 236 10.1038/nature08673 20075918
48 Mothet J.P. Parent A.T. Wolosker H. Brady R.O. Jr Linden D.J. Ferris C.D. Rogawski M.A. Snyder S.H. D -Serine is an endogenous ligand for the glycine site of the N -methyl- D -aspartate receptor. Proc. Natl. Acad. Sci. 2000 97 9 4926 4931 10.1073/pnas.97.9.4926 10781100
49 Coyle J.T. Balu D. Wolosker H. d-serine, the shape-shifting NMDA receptor co-agonist. Neurochem. Res. 2020 45 6 1344 1353 10.1007/s11064-020-03014-1 32189130
50 Wolosker H. Balu D.T. Coyle J.T. The rise and fall of the d -serine-mediated gliotransmission hypothesis. Trends Neurosci. 2016 39 11 712 721 10.1016/j.tins.2016.09.007 27742076
51 Papouin T. Dunphy J.M. Tolman M. Dineley K.T. Haydon P.G. Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness. Neuron 2017 94 4 840 854.e7 10.1016/j.neuron.2017.04.021 28479102
52 Koh W. Park M. Chun Y.E. Lee J. Shim H.S. Park M.G. Kim S. Sa M. Joo J. Kang H. Oh S.J. Woo J. Chun H. Lee S.E. Hong J. Feng J. Li Y. Ryu H. Cho J. Lee C.J. Astrocytes render memory flexible by releasing D-serine and regulating NMDA receptor tone in the hippocampus. Biol. Psychiatry 2022 91 8 740 752 10.1016/j.biopsych.2021.10.012 34952697
53 Huang A.Y.S. Woo J. Sardar D. Lozzi B. Bosquez Huerta N.A. Lin C.C.J. Felice D. Jain A. Paulucci-Holthauzen A. Deneen B. Region-specific transcriptional control of astrocyte function oversees local circuit activities. Neuron 2020 106 6 992 1008.e9 10.1016/j.neuron.2020.03.025 32320644
54 Suzuki A. Stern S.A. Bozdagi O. Huntley G.W. Walker R.H. Magistretti P.J. Alberini C.M. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 2011 144 5 810 823 10.1016/j.cell.2011.02.018 21376239
55 González-Gutiérrez A. Ibacache A. Esparza A. Barros L.F. Sierralta J. Neuronal lactate levels depend on glia‐derived lactate during high brain activity in Drosophila. Glia 2020 68 6 1213 1227 10.1002/glia.23772 31876077
56 Vezzoli E. Calì C. De Roo M. Ponzoni L. Sogne E. Gagnon N. Francolini M. Braida D. Sala M. Muller D. Falqui A. Magistretti P.J. Ultrastructural evidence for a role of astrocytes and glycogen-derived lactate in learning-dependent synaptic stabilization. Cereb. Cortex 2020 30 4 2114 2127 10.1093/cercor/bhz226 31807747
57 Descalzi G. Gao V. Steinman M.Q. Suzuki A. Alberini C.M. Lactate from astrocytes fuels learning-induced mRNA translation in excitatory and inhibitory neurons. Commun. Biol. 2019 2 1 247 10.1038/s42003-019-0495-2 31286064
58 Herkenham M. Lynn A.B. Little M.D. Johnson M.R. Melvin L.S. de Costa B.R. Rice K.C. Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. 1990 87 5 1932 1936 10.1073/pnas.87.5.1932 2308954
59 Navarrete M. Araque A. Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. Neuron 2010 68 1 113 126 10.1016/j.neuron.2010.08.043 20920795
60 Robin L.M. Oliveira da Cruz J.F. Langlais V.C. Martin-Fernandez M. Metna-Laurent M. Busquets-Garcia A. Bellocchio L. Soria-Gomez E. Papouin T. Varilh M. Sherwood M.W. Belluomo I. Balcells G. Matias I. Bosier B. Drago F. Van Eeckhaut A. Smolders I. Georges F. Araque A. Panatier A. Oliet S.H.R. Marsicano G. Astroglial CB1 receptors determine synaptic d-serine availability to enable recognition memory. Neuron 2018 98 5 935 944.e5 10.1016/j.neuron.2018.04.034 29779943
61 Zhou Z. Okamoto K. Onodera J. Hiragi T. Andoh M. Ikawa M. Tanaka K.F. Ikegaya Y. Koyama R. Astrocytic cAMP modulates memory via synaptic plasticity. Proc. Natl. Acad. Sci. 2021 118 3 e2016584118 10.1073/pnas.2016584118 33452135
62 Chi S. Cui Y. Wang H. Jiang J. Zhang T. Sun S. Zhou Z. Zhong Y. Xiao B. Astrocytic Piezo1-mediated mechanotransduction determines adult neurogenesis and cognitive functions. Neuron 2022 110 18 2984 2999.e8 10.1016/j.neuron.2022.07.010 35963237
63 Henneberger C. Bard L. Panatier A. Reynolds J.P. Kopach O. Medvedev N.I. Minge D. Herde M.K. Anders S. Kraev I. Heller J.P. Rama S. Zheng K. Jensen T.P. Sanchez-Romero I. Jackson C.J. Janovjak H. Ottersen O.P. Nagelhus E.A. Oliet S.H.R. Stewart M.G. Nägerl U.V. Rusakov D.A. LTP induction boosts glutamate spillover by driving withdrawal of perisynaptic astroglia. Neuron 2020 108 5 919 936.e11 10.1016/j.neuron.2020.08.030 32976770
64 Vignoli B. Sansevero G. Sasi M. Rimondini R. Blum R. Bonaldo V. Biasini E. Santi S. Berardi N. Lu B. Canossa M. Astrocytic microdomains from mouse cortex gain molecular control over long-term information storage and memory retention. Commun. Biol. 2021 4 1 1152 10.1038/s42003-021-02678-x 34611268
65 Dudek S.M. Bear M.F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc. Natl. Acad. Sci. 1992 89 10 4363 4367 10.1073/pnas.89.10.4363 1350090
66 Han J. Kesner P. Metna-Laurent M. Duan T. Xu L. Georges F. Koehl M. Abrous D.N. Mendizabal-Zubiaga J. Grandes P. Liu Q. Bai G. Wang W. Xiong L. Ren W. Marsicano G. Zhang X. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell 2012 148 5 1039 1050 10.1016/j.cell.2012.01.037 22385967
67 Navarrete M. Araque A. Endocannabinoids mediate neuron-astrocyte communication. Neuron 2008 57 6 883 893 10.1016/j.neuron.2008.01.029 18367089
68 Pinto-Duarte A. Roberts A.J. Ouyang K. Sejnowski T.J. Impairments in remote memory caused by the lack of Type 2 IP 3 receptors. Glia 2019 67 10 1976 1989 10.1002/glia.23679 31348567
69 Navarrete M. Cuartero M.I. Palenzuela R. Draffin J.E. Konomi A. Serra I. Colié S. Castaño-Castaño S. Hasan M.T. Nebreda Á.R. Esteban J.A. Astrocytic p38α MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory. Nat. Commun. 2019 10 1 2968 10.1038/s41467-019-10830-9 31273206
70 Soto M. Cai W. Konishi M. Kahn C.R. Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc. Natl. Acad. Sci. 2019 116 13 6379 6384 10.1073/pnas.1817391116 30765523
71 Noriega-Prieto J.A. Maglio L.E. Zegarra-Valdivia J.A. Pignatelli J. Fernandez A.M. Martinez-Rachadell L. Fernandes J. Núñez Á. Araque A. Torres-Alemán I. Fernández de Sevilla D. Astrocytic IGF-IRs induce adenosine-mediated inhibitory downregulation and improve sensory discrimination. J. Neurosci. 2021 41 22 4768 4781 10.1523/JNEUROSCI.0005-21.2021 33911021
72 Brzosko Z. Mierau S.B. Paulsen O. Neuromodulation of spike-timing-dependent plasticity: Past, present, and future. Neuron 2019 103 4 563 581 10.1016/j.neuron.2019.05.041 31437453
73 Falcón-Moya R. Pérez-Rodríguez M. Prius-Mengual J. Andrade-Talavera Y. Arroyo-García L.E. Pérez-Artés R. Mateos-Aparicio P. Guerra-Gomes S. Oliveira J.F. Flores G. Rodríguez-Moreno A. Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development. Nat. Commun. 2020 11 1 4388 10.1038/s41467-020-18024-4 32873805
74 Martínez-Gallego I. Pérez-Rodríguez M. Coatl-Cuaya H. Flores G. Rodríguez-Moreno A. Adenosine and astrocytes determine the developmental dynamics of spike timing-dependent plasticity in the somatosensory cortex. J. Neurosci. 2022 42 31 6038 6052 10.1523/JNEUROSCI.0115-22.2022 35768208
75 Min R. Nevian T. Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. Nat. Neurosci. 2012 15 5 746 753 10.1038/nn.3075 22446881
76 Jones E.V. Bouvier D.S. Astrocyte-secreted matricellular proteins in CNS remodelling during development and disease. Neural Plast. 2014 2014 1 12 10.1155/2014/321209 24551460
77 Risher W.C. Kim N. Koh S. Choi J.E. Mitev P. Spence E.F. Pilaz L.J. Wang D. Feng G. Silver D.L. Soderling S.H. Yin H.H. Eroglu C. Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J. Cell Biol. 2018 217 10 3747 3765 10.1083/jcb.201802057 30054448
78 Takano T. Wallace J.T. Baldwin K.T. Purkey A.M. Uezu A. Courtland J.L. Soderblom E.J. Shimogori T. Maness P.F. Eroglu C. Soderling S.H. Chemico-genetic discovery of astrocytic control of inhibition in vivo. Nature 2020 588 7837 296 302 10.1038/s41586-020-2926-0 33177716
79 Chung W.S. Clarke L.E. Wang G.X. Stafford B.K. Sher A. Chakraborty C. Joung J. Foo L.C. Thompson A. Chen C. Smith S.J. Barres B.A. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 2013 504 7480 394 400 10.1038/nature12776 24270812
80 Lee J.H. Kim J. Noh S. Lee H. Lee S.Y. Mun J.Y. Park H. Chung W.S. Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature 2021 590 7847 612 617 10.1038/s41586-020-03060-3 33361813
81 Vainchtein I.D. Chin G. Cho F.S. Kelley K.W. Miller J.G. Chien E.C. Liddelow S.A. Nguyen P.T. Nakao-Inoue H. Dorman L.C. Akil O. Joshita S. Barres B.A. Paz J.T. Molofsky A.B. Molofsky A.V. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 2018 359 6381 1269 1273 10.1126/science.aal3589 29420261
82 Wang Y. Fu W.Y. Cheung K. Hung K.W. Chen C. Geng H. Yung W.H. Qu J.Y. Fu A.K.Y. Ip N.Y. Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus. Proc. Natl. Acad. Sci. 2021 118 1 e2020810118 10.1073/pnas.2020810118 33443211
83 Koeppen J. Nguyen A.Q. Nikolakopoulou A.M. Garcia M. Hanna S. Woodruff S. Figueroa Z. Obenaus A. Ethell I.M. Functional consequences of synapse remodeling following astrocyte-specific regulation of ephrin-B1 in the adult hippocampus. J. Neurosci. 2018 38 25 5710 5726 10.1523/JNEUROSCI.3618-17.2018 29793972
84 Tan Z. Liu Y. Xi W. Lou H. Zhu L. Guo Z. Mei L. Duan S. Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons. Nat. Commun. 2017 8 1 13772 10.1038/ncomms13772 28128211
85 Poskanzer K.E. Yuste R. Astrocytes regulate cortical state switching in vivo. Proc. Natl. Acad. Sci. 2016 113 19 E2675 E2684 10.1073/pnas.1520759113 27122314
86 Ji D. Wilson M.A. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nat. Neurosci. 2007 10 1 100 107 10.1038/nn1825 17173043
87 Lee H.S. Ghetti A. Pinto-Duarte A. Wang X. Dziewczapolski G. Galimi F. Huitron-Resendiz S. Piña-Crespo J.C. Roberts A.J. Verma I.M. Sejnowski T.J. Heinemann S.F. Astrocytes contribute to gamma oscillations and recognition memory. Proc. Natl. Acad. Sci. 2014 111 32 E3343 E3352 10.1073/pnas.1410893111 25071179
88 Brockett A.T. Kane G.A. Monari P.K. Briones B.A. Vigneron P.A. Barber G.A. Bermudez A. Dieffenbach U. Kloth A.D. Buschman T.J. Gould E. Evidence supporting a role for astrocytes in the regulation of cognitive flexibility and neuronal oscillations through the Ca2+ binding protein S100β. PLoS One 2018 13 4 e0195726 10.1371/journal.pone.0195726 29664924
89 Sardinha V.M. Guerra-Gomes S. Caetano I. Tavares G. Martins M. Reis J.S. Correia J.S. Teixeira-Castro A. Pinto L. Sousa N. Oliveira J.F. Astrocytic signaling supports hippocampal–prefrontal theta synchronization and cognitive function. Glia 2017 65 12 1944 1960 10.1002/glia.23205 28885722
90 Mederos S. Sánchez-Puelles C. Esparza J. Valero M. Ponomarenko A. Perea G. GABAergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors. Nat. Neurosci. 2021 24 1 82 92 10.1038/s41593-020-00752-x 33288910
91 Luo L. Architectures of neuronal circuits. Science 2021 373 6559 eabg7285 10.1126/science.abg7285 34516844
92 Martin-Fernandez M. Jamison S. Robin L.M. Zhao Z. Martin E.D. Aguilar J. Benneyworth M.A. Marsicano G. Araque A. Synapse-specific astrocyte gating of amygdala-related behavior. Nat. Neurosci. 2017 20 11 1540 1548 10.1038/nn.4649 28945222
93 Serra I. Esparza J. Delgado L. Martín-Monteagudo C. Puigròs M. Podlesniy P. Trullás R. Navarrete M. Ca2+-modulated photoactivatable imaging reveals neuron-astrocyte glutamatergic circuitries within the nucleus accumbens. Nat. Commun. 2022 13 1 5272 10.1038/s41467-022-33020-6 36071061
94 Burgess N. Maguire E.A. O’Keefe J. The human hippocampus and spatial and episodic memory. Neuron 2002 35 4 625 641 10.1016/S0896-6273(02)00830-9 12194864
95 Jourdain P. Bergersen L.H. Bhaukaurally K. Bezzi P. Santello M. Domercq M. Matute C. Tonello F. Gundersen V. Volterra A. Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 2007 10 3 331 339 10.1038/nn1849 17310248
96 Savtchouk I. Di Castro M.A. Ali R. Stubbe H. Luján R. Volterra A. Circuit-specific control of the medial entorhinal inputs to the dentate gyrus by atypical presynaptic NMDARs activated by astrocytes. Proc. Natl. Acad. Sci. 2019 116 27 13602 13610 10.1073/pnas.1816013116 31152131
97 Zhao J. Sun J. Zheng Y. Zheng Y. Shao Y. Li Y. Fei F. Xu C. Liu X. Wang S. Ruan Y. Liu J. Duan S. Chen Z. Wang Y. Activated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase. Nat. Commun. 2022 13 1 7136 10.1038/s41467-022-34662-2 36414629
98 Kol A. Adamsky A. Groysman M. Kreisel T. London M. Goshen I. Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning. Nat. Neurosci. 2020 23 10 1229 1239 10.1038/s41593-020-0679-6 32747787
99 Hasan M. Kanna M.S. Jun W. Ramkrishnan A.S. Iqbal Z. Lee Y. Li Y. Schema‐like learning and memory consolidation acting through myelination. FASEB J. 2019 33 11 11758 11775 10.1096/fj.201900910R 31366238
100 Liu S. Wong H.Y. Xie L. Iqbal Z. Lei Z. Fu Z. Lam Y.Y. Ramkrishnan A.S. Li Y. Astrocytes in CA1 modulate schema establishment in the hippocampal-cortical neuron network. BMC Biol. 2022 20 1 250 10.1186/s12915-022-01445-6 36352395
101 Lei Z. Xie L. Li C.H. Lam Y.Y. Ramkrishnan A.S. Fu Z. Zeng X. Liu S. Iqbal Z. Li Y. Chemogenetic activation of astrocytes in the basolateral amygdala contributes to fear memory formation by modulating the amygdala-prefrontal cortex communication. Int. J. Mol. Sci. 2022 23 11 6092 10.3390/ijms23116092 35682767
102 Doron A. Rubin A. Benmelech-Chovav A. Benaim N. Carmi T. Refaeli R. Novick N. Kreisel T. Ziv Y. Goshen I. Hippocampal astrocytes encode reward location. Nature 2022 609 7928 772 778 10.1038/s41586-022-05146-6 36045289
103 Curreli S. Bonato J. Romanzi S. Panzeri S. Fellin T. Complementary encoding of spatial information in hippocampal astrocytes. PLoS Biol. 2022 20 3 e3001530 10.1371/journal.pbio.3001530 35239646
104 Bellmund J.L.S. Gärdenfors P. Moser E.I. Doeller C.F. Navigating cognition: Spatial codes for human thinking. Science 2018 362 6415 eaat6766 10.1126/science.aat6766 30409861
105 Hartley T. Lever C. Burgess N. O’Keefe J. Space in the brain: How the hippocampal formation supports spatial cognition. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2014 369 1635 20120510 10.1098/rstb.2012.0510 24366125
106 Nagai J. Bellafard A. Qu Z. Yu X. Ollivier M. Gangwani M.R. Diaz-Castro B. Coppola G. Schumacher S.M. Golshani P. Gradinaru V. Khakh B.S. Specific and behaviorally consequential astrocyte Gq GPCR signaling attenuation in vivo with iβARK. Neuron 2021 109 14 2256 2274.e9 10.1016/j.neuron.2021.05.023 34139149
107 Pannasch U. Vargová L. Reingruber J. Ezan P. Holcman D. Giaume C. Syková E. Rouach N. Astroglial networks scale synaptic activity and plasticity. Proc. Natl. Acad. Sci. 2011 108 20 8467 8472 10.1073/pnas.1016650108 21536893
108 Hösli L. Binini N. Ferrari K.D. Thieren L. Looser Z.J. Zuend M. Zanker H.S. Berry S. Holub M. Möbius W. Ruhwedel T. Nave K.A. Giaume C. Weber B. Saab A.S. Decoupling astrocytes in adult mice impairs synaptic plasticity and spatial learning. Cell Rep. 2022 38 10 110484 10.1016/j.celrep.2022.110484 35263595
109 Tao X.D. Liu Z.R. Zhang Y.Q. Zhang X.H. Connexin43 hemichannels contribute to working memory and excitatory synaptic transmission of pyramidal neurons in the prefrontal cortex of rats. Life Sci. 2021 286 120049 10.1016/j.lfs.2021.120049 34662549
110 Herzine A. Sekkat G. Kaminski S. Calcagno G. Boschi-Muller S. Safi H. Corbier C. Siest S. Claudepierre T. Yen F.T. Lipolysis-stimulated lipoprotein receptor acts as sensor to regulate apoe release in astrocytes. Int. J. Mol. Sci. 2022 23 15 8630 10.3390/ijms23158630 35955777
111 El Hajj A. Herzine A. Calcagno G. Désor F. Djelti F. Bombail V. Denis I. Oster T. Malaplate C. Vigier M. Kaminski S. Pauron L. Corbier C. Yen F.T. Lanhers M.C. Claudepierre T. Targeted suppression of lipoprotein receptor LSR in astrocytes leads to olfactory and memory deficits in mice. Int. J. Mol. Sci. 2022 23 4 2049 10.3390/ijms23042049 35216163
112 Baier M.P. Nagaraja R.Y. Yarbrough H.P. Owen D.B. Masingale A.M. Ranjit R. Stiles M.A. Murphy A. Agbaga M.P. Ahmad M. Sherry D.M. Kinter M.T. Van Remmen H. Logan S. Selective ablation of Sod2 in astrocytes induces sex-specific effects on cognitive function, d-serine availability, and astrogliosis. J. Neurosci. 2022 42 31 5992 6006 10.1523/JNEUROSCI.2543-21.2022 35760531
113 Curie A. Sacco S. Bussy G. de Saint Martin A. Boddaert N. Chanraud S. Meresse I. Chelly J. Zilbovicius M. des Portes V. Impairment of cerebello-thalamo-frontal pathway in Rab-GDI mutated patients with pure mental deficiency. Eur. J. Med. Genet. 2009 52 1 6 13 10.1016/j.ejmg.2008.09.003 18992375
114 Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 2009 10 8 513 525 10.1038/nrm2728 19603039
115 D’Adamo P. Horvat A. Gurgone A. Mignogna M.L. Bianchi V. Masetti M. Ripamonti M. Taverna S. Velebit J. Malnar M. Muhič M. Fink K. Bachi A. Restuccia U. Belloli S. Moresco R.M. Mercalli A. Piemonti L. Potokar M. Bobnar S.T. Kreft M. Chowdhury H.H. Stenovec M. Vardjan N. Zorec R. Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse. Metabolism 2021 116 154463 10.1016/j.metabol.2020.154463 33309713
116 Adamsky A. Kol A. Kreisel T. Doron A. Ozeri-Engelhard N. Melcer T. Refaeli R. Horn H. Regev L. Groysman M. London M. Goshen I. Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell 2018 174 1 59 71.e14 10.1016/j.cell.2018.05.002 29804835
117 Li Y. Li L. Wu J. Zhu Z. Feng X. Qin L. Zhu Y. Sun L. Liu Y. Qiu Z. Duan S. Yu Y.Q. Activation of astrocytes in hippocampus decreases fear memory through adenosine A1 receptors. eLife 2020 9 e57155 10.7554/eLife.57155 32869747
118 Fan X.C. Ma C.N. Song J.C. Liao Z.H. Huang N. Liu X. Ma L. Rac1 signaling in amygdala astrocytes regulates fear memory acquisition and retrieval. Neurosci. Bull. 2021 37 7 947 958 10.1007/s12264-021-00677-w 33909243
119 Li W.P. Su X.H. Hu N.Y. Hu J. Li X.W. Yang J.M. Gao T.M. Astrocytes mediate cholinergic regulation of adult hippocampal neurogenesis and memory through M1 muscarinic receptor. Biol. Psychiatry 2022 92 12 984 998 10.1016/j.biopsych.2022.04.019 35787318
120 Badia-Soteras A. Heistek T.S. Kater M.S.J. Mak A. Negrean A. van den Oever M.C. Mansvelder H.D. Khakh B.S. Min R. Smit A.B. Verheijen M.H.G. Retraction of astrocyte leaflets from the synapse enhances fear memory. Biol. Psychiatry 2023 94 3 226 238 10.1016/j.biopsych.2022.10.013 36702661
121 Zhang K. Förster R. He W. Liao X. Li J. Yang C. Qin H. Wang M. Ding R. Li R. Jian T. Wang Y. Zhang J. Yang Z. Jin W. Zhang Y. Qin S. Lu Y. Chen T. Stobart J. Weber B. Adelsberger H. Konnerth A. Chen X. Fear learning induces α7-nicotinic acetylcholine receptor-mediated astrocytic responsiveness that is required for memory persistence. Nat. Neurosci. 2021 24 12 1686 1698 10.1038/s41593-021-00949-8 34782794
122 Tertil M. Skupio U. Barut J. Dubovyk V. Wawrzczak-Bargiela A. Soltys Z. Golda S. Kudla L. Wiktorowska L. Szklarczyk K. Korostynski M. Przewlocki R. Slezak M. Glucocorticoid receptor signaling in astrocytes is required for aversive memory formation. Transl. Psychiatry 2018 8 1 255 10.1038/s41398-018-0300-x 30487639
123 Iqbal Z. Liu S. Lei Z. Ramkrishnan A.S. Akter M. Li Y. Astrocyte L-Lactate signaling in the acc regulates visceral pain aversive memory in rats. Cells 2022 12 1 26 10.3390/cells12010026 36611820
124 Iqbal Z. Lei Z. Ramkrishnan A.S. Liu S. Hasan M. Akter M. Lam Y.Y. Li Y. Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats. Commun. Biol. 2023 6 1 10 10.1038/s42003-022-04405-6 36604595
125 Cheung G. Bataveljic D. Visser J. Kumar N. Moulard J. Dallérac G. Mozheiko D. Rollenhagen A. Ezan P. Mongin C. Chever O. Bemelmans A.P. Lübke J. Leray I. Rouach N. Physiological synaptic activity and recognition memory require astroglial glutamine. Nat. Commun. 2022 13 1 753 10.1038/s41467-022-28331-7 35136061
126 Ray S. Valekunja U.K. Stangherlin A. Howell S.A. Snijders A.P. Damodaran G. Reddy A.B. Circadian rhythms in the absence of the clock gene Bmal1. Science 2020 367 6479 800 806 10.1126/science.aaw7365 32054765
127 Barca-Mayo O. Pons-Espinal M. Follert P. Armirotti A. Berdondini L. De Pietri Tonelli D. Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling. Nat. Commun. 2017 8 1 14336 10.1038/ncomms14336 28186121
128 Sofroniew M.V. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 2009 32 12 638 647 10.1016/j.tins.2009.08.002 19782411
129 Bellaver B. Souza D.G. Souza D.O. Quincozes-Santos A. Hippocampal astrocyte cultures from adult and aged rats reproduce changes in glial functionality observed in the aging brain. Mol. Neurobiol. 2017 54 4 2969 2985 10.1007/s12035-016-9880-8 27026184
130 Murphy-Royal C. Gordon G.R. Bains J.S. Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress. Glia 2019 67 10 1806 1820 10.1002/glia.23610 30889320
131 Tynan R.J. Beynon S.B. Hinwood M. Johnson S.J. Nilsson M. Woods J.J. Walker F.R. Chronic stress-induced disruption of the astrocyte network is driven by structural atrophy and not loss of astrocytes. Acta Neuropathol. 2013 126 1 75 91 10.1007/s00401-013-1102-0 23512378
132 Jo S. Yarishkin O. Hwang Y.J. Chun Y.E. Park M. Woo D.H. Bae J.Y. Kim T. Lee J. Chun H. Park H.J. Lee D.Y. Hong J. Kim H.Y. Oh S.J. Park S.J. Lee H. Yoon B.E. Kim Y. Jeong Y. Shim I. Bae Y.C. Cho J. Kowall N.W. Ryu H. Hwang E. Kim D. Lee C.J. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat. Med. 2014 20 8 886 896 10.1038/nm.3639 24973918
133 Chun H. Im H. Kang Y.J. Kim Y. Shin J.H. Won W. Lim J. Ju Y. Park Y.M. Kim S. Lee S.E. Lee J. Woo J. Hwang Y. Cho H. Jo S. Park J.H. Kim D. Kim D.Y. Seo J.S. Gwag B.J. Kim Y.S. Park K.D. Kaang B.K. Cho H. Ryu H. Lee C.J. Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2− production. Nat. Neurosci. 2020 23 12 1555 1566 10.1038/s41593-020-00735-y 33199896
134 Pereira J.B. Janelidze S. Smith R. Mattsson-Carlgren N. Palmqvist S. Teunissen C.E. Zetterberg H. Stomrud E. Ashton N.J. Blennow K. Hansson O. Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer’s disease. Brain 2021 144 11 3505 3516 10.1093/brain/awab223 34259835
135 Bettcher B.M. Olson K.E. Carlson N.E. McConnell B.V. Boyd T. Adame V. Solano D.A. Anton P. Markham N. Thaker A.A. Jensen A.M. Dallmann E.N. Potter H. Coughlan C. Astrogliosis and episodic memory in late life: Higher GFAP is related to worse memory and white matter microstructure in healthy aging and Alzheimer’s disease. Neurobiol. Aging 2021 103 68 77 10.1016/j.neurobiolaging.2021.02.012 33845398
136 Iliff J.J. Wang M. Liao Y. Plogg B.A. Peng W. Gundersen G.A. Benveniste H. Vates G.E. Deane R. Goldman S.A. Nagelhus E.A. Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 2012 4 147 147ra111 10.1126/scitranslmed.3003748 22896675
137 Xu Z. Xiao N. Chen Y. Huang H. Marshall C. Gao J. Cai Z. Wu T. Hu G. Xiao M. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol. Neurodegener. 2015 10 1 58 10.1186/s13024-015-0056-1 26526066
138 Du Z. Song Y. Chen X. Zhang W. Zhang G. Li H. Chang L. Wu Y. Knockdown of astrocytic Grin2a aggravates β‐amyloid‐induced memory and cognitive deficits through regulating nerve growth factor. Aging Cell 2021 20 8 e13437 10.1111/acel.13437 34291567
139 Ju Y.H. Bhalla M. Hyeon S.J. Oh J.E. Yoo S. Chae U. Kwon J. Koh W. Lim J. Park Y.M. Lee J. Cho I.J. Lee H. Ryu H. Lee C.J. Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s disease. Cell Metab. 2022 34 8 1104 1120.e8 10.1016/j.cmet.2022.05.011 35738259
140 Richetin K. Steullet P. Pachoud M. Perbet R. Parietti E. Maheswaran M. Eddarkaoui S. Bégard S. Pythoud C. Rey M. Caillierez R. Q Do K. Halliez S. Bezzi P. Buée L. Leuba G. Colin M. Toni N. Déglon N. Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer’s disease. Nat. Neurosci. 2020 23 12 1567 1579 10.1038/s41593-020-00728-x 33169029
141 Holtzman D.M. Herz J. Bu G. Apolipoprotein E and apolipoprotein E receptors: Normal biology and roles in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2012 2 3 a006312 10.1101/cshperspect.a006312 22393530
142 Pitas R.E. Boyles J.K. Lee S.H. Foss D. Mahley R.W. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim. Biophys. Acta. Lipids Lipid Metab. 1987 917 1 148 161 10.1016/0005-2760(87)90295-5 3539206
143 Montagne A. Nation D.A. Sagare A.P. Barisano G. Sweeney M.D. Chakhoyan A. Pachicano M. Joe E. Nelson A.R. D’Orazio L.M. Buennagel D.P. Harrington M.G. Benzinger T.L.S. Fagan A.M. Ringman J.M. Schneider L.S. Morris J.C. Reiman E.M. Caselli R.J. Chui H.C. Tcw J. Chen Y. Pa J. Conti P.S. Law M. Toga A.W. Zlokovic B.V. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 2020 581 7806 71 76 10.1038/s41586-020-2247-3 32376954
144 Sienski G. Narayan P. Bonner J.M. Kory N. Boland S. Arczewska A.A. Ralvenius W.T. Akay L. Lockshin E. He L. Milo B. Graziosi A. Baru V. Lewis C.A. Kellis M. Sabatini D.M. Tsai L.H. Lindquist S. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Sci. Transl. Med. 2021 13 583 eaaz4564 10.1126/scitranslmed.aaz4564 33658354
145 Saroja S.R. Gorbachev K. Julia T.C.W. Goate A.M. Pereira A.C. Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation. Proc. Natl. Acad. Sci. 2022 119 34 e2108870119 10.1073/pnas.2108870119 35969759
146 Tcw J. Qian L. Pipalia N.H. Chao M.J. Liang S.A. Shi Y. Jain B.R. Bertelsen S.E. Kapoor M. Marcora E. Sikora E. Andrews E.J. Martini A.C. Karch C.M. Head E. Holtzman D.M. Zhang B. Wang M. Maxfield F.R. Poon W.W. Goate A.M. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell 2022 185 13 2213 2233.e25 10.1016/j.cell.2022.05.017 35750033
147 Wang C. Xiong M. Gratuze M. Bao X. Shi Y. Andhey P.S. Manis M. Schroeder C. Yin Z. Madore C. Butovsky O. Artyomov M. Ulrich J.D. Holtzman D.M. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron 2021 109 10 1657 1674 10.1016/j.neuron.2021.03.024 33831349
148 Le Douce J. Maugard M. Veran J. Matos M. Jégo P. Vigneron P.A. Faivre E. Toussay X. Vandenberghe M. Balbastre Y. Piquet J. Guiot E. Tran N.T. Taverna M. Marinesco S. Koyanagi A. Furuya S. Gaudin-Guérif M. Goutal S. Ghettas A. Pruvost A. Bemelmans A.P. Gaillard M.C. Cambon K. Stimmer L. Sazdovitch V. Duyckaerts C. Knott G. Hérard A.S. Delzescaux T. Hantraye P. Brouillet E. Cauli B. Oliet S.H.R. Panatier A. Bonvento G. Impairment of glycolysis-derived l-serine production in astrocytes contributes to cognitive deficits in alzheimer’s disease. Cell Metab. 2020 31 3 503 517.e8 10.1016/j.cmet.2020.02.004 32130882
149 Bosson A. Paumier A. Boisseau S. Jacquier-Sarlin M. Buisson A. Albrieux M. TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide. Mol. Neurodegener. 2017 12 1 53 10.1186/s13024-017-0194-8 28683776
150 Paumier A. Boisseau S. Jacquier-Sarlin M. Pernet-Gallay K. Buisson A. Albrieux M. Astrocyte–neuron interplay is critical for Alzheimer’s disease pathogenesis and is rescued by TRPA1 channel blockade. Brain 2022 145 1 388 405 10.1093/brain/awab281 34302466
151 Lia A. Sansevero G. Chiavegato A. Sbrissa M. Pendin D. Mariotti L. Pozzan T. Berardi N. Carmignoto G. Fasolato C. Zonta M. Rescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in female mice modelling Alzheimer’s disease. Nat. Commun. 2023 14 1 1590 10.1038/s41467-023-37240-2 36949142
152 Reichenbach N. Delekate A. Breithausen B. Keppler K. Poll S. Schulte T. Peter J. Plescher M. Hansen J.N. Blank N. Keller A. Fuhrmann M. Henneberger C. Halle A. Petzold G.C. P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model. J. Exp. Med. 2018 215 6 1649 1663 10.1084/jem.20171487 29724785
153 Raha S. Ghosh A. Dutta D. Patel D.R. Pahan K. Activation of PPARα enhances astroglial uptake and degradation of β-amyloid. Sci. Signal. 2021 14 706 eabg4747 10.1126/scisignal.abg4747 34699252
154 McAlpine C.S. Park J. Griciuc A. Kim E. Choi S.H. Iwamoto Y. Kiss M.G. Christie K.A. Vinegoni C. Poller W.C. Mindur J.E. Chan C.T. He S. Janssen H. Wong L.P. Downey J. Singh S. Anzai A. Kahles F. Jorfi M. Feruglio P.F. Sadreyev R.I. Weissleder R. Kleinstiver B.P. Nahrendorf M. Tanzi R.E. Swirski F.K. Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease. Nature 2021 595 7869 701 706 10.1038/s41586-021-03734-6 34262178
155 Jiwaji Z. Tiwari S.S. Avilés-Reyes R.X. Hooley M. Hampton D. Torvell M. Johnson D.A. McQueen J. Baxter P. Sabari-Sankar K. Qiu J. He X. Fowler J. Febery J. Gregory J. Rose J. Tulloch J. Loan J. Story D. McDade K. Smith A.M. Greer P. Ball M. Kind P.C. Matthews P.M. Smith C. Dando O. Spires-Jones T.L. Johnson J.A. Chandran S. Hardingham G.E. Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nat. Commun. 2022 13 1 135 10.1038/s41467-021-27702-w 35013236
156 Popov A. Brazhe A. Denisov P. Sutyagina O. Li L. Lazareva N. Verkhratsky A. Semyanov A. Astrocyte dystrophy in ageing brain parallels impaired synaptic plasticity. Aging Cell 2021 20 3 e13334 10.1111/acel.13334 33675569
157 Verkhratsky A. Augusto-Oliveira M. Pivoriūnas A. Popov A. Brazhe A. Semyanov A. Astroglial asthenia and loss of function, rather than reactivity, contribute to the ageing of the brain. Pflugers Arch. 2021 473 5 753 774 10.1007/s00424-020-02465-3 32979108
158 Ding F. Liang S. Li R. Yang Z. He Y. Yang S. Duan Q. Zhang J. Lyu J. Zhou Z. Huang M. Wang H. Li J. Yang C. Wang Y. Gong M. Chen S. Jia H. Chen X. Liao X. Fu L. Zhang K. Astrocytes exhibit diverse Ca2+ changes at subcellular domains during brain aging. Front. Aging Neurosci. 2022 14 1029533 10.3389/fnagi.2022.1029533 36389078
159 Soreq L. Rose J. Soreq E. Hardy J. Trabzuni D. Cookson M.R. Smith C. Ryten M. Patani R. Ule J. Major shifts in glial regional identity are a transcriptional hallmark of human brain aging. Cell Rep. 2017 18 2 557 570 10.1016/j.celrep.2016.12.011 28076797
160 Clarke L.E. Liddelow S.A. Chakraborty C. Münch A.E. Heiman M. Barres B.A. Normal aging induces A1-like astrocyte reactivity. Proc. Natl. Acad. Sci. 2018 115 8 E1896 E1905 10.1073/pnas.1800165115 29437957
161 Allen W.E. Blosser T.R. Sullivan Z.A. Dulac C. Zhuang X. Molecular and spatial signatures of mouse brain aging at single-cell resolution. Cell 2023 186 1 194 208.e18 10.1016/j.cell.2022.12.010 36580914
162 Preininger M.K. Kaufer D. Blood-brain barrier dysfunction and astrocyte senescence as reciprocal drivers of neuropathology in aging. Int. J. Mol. Sci. 2022 23 11 6217 10.3390/ijms23116217 35682895
163 Cohen J. Torres C. Astrocyte senescence: Evidence and significance. Aging Cell 2019 18 3 e12937 10.1111/acel.12937 30815970
164 Boisvert M.M. Erikson G.A. Shokhirev M.N. Allen N.J. The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep. 2018 22 1 269 285 10.1016/j.celrep.2017.12.039 29298427
165 Orre M. Kamphuis W. Osborn L.M. Melief J. Kooijman L. Huitinga I. Klooster J. Bossers K. Hol E.M. Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol. Aging 2014 35 1 1 14 10.1016/j.neurobiolaging.2013.07.008 23954174
166 Boender A.J. Bontempi L. Nava L. Pelloux Y. Tonini R. Striatal astrocytes shape behavioral flexibility via regulation of the glutamate transporter EAAT2. Biol. Psychiatry 2021 89 11 1045 1057 10.1016/j.biopsych.2020.11.015 33516457
167 Sharma A. Kazim S.F. Larson C.S. Ramakrishnan A. Gray J.D. McEwen B.S. Rosenberg P.A. Shen L. Pereira A.C. Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer’s molecular signatures. Proc. Natl. Acad. Sci. 2019 116 43 21800 21811 10.1073/pnas.1903566116 31591195
168 Yang Z. Gong M. Jian T. Li J. Yang C. Ma Q. Deng P. Wang Y. Huang M. Wang H. Yang S. Chen X. Yu Z. Wang M. Chen C. Zhang K. Engrafted glial progenitor cells yield long-term integration and sensory improvement in aged mice. Stem Cell Res. Ther. 2022 13 1 285 10.1186/s13287-022-02959-0 35765112
169 Xu X. Shen X. Wang J. Feng W. Wang M. Miao X. Wu Q. Wu L. Wang X. Ma Y. Wu S. Bao X. Wang W. Wang Y. Huang Z. YAP prevents premature senescence of astrocytes and cognitive decline of Alzheimer’s disease through regulating CDK6 signaling. Aging Cell 2021 20 9 e13465 10.1111/acel.13465 34415667
170 Raihan O. Brishti A. Molla M.R. Li W. Zhang Q. Xu P. Khan M.I. Zhang J. Liu Q. The age-dependent elevation of miR-335-3p leads to reduced cholesterol and impaired memory in brain. Neuroscience 2018 390 160 173 10.1016/j.neuroscience.2018.08.003 30125687
171 Patel B.N. Dunn R.J. Jeong S.Y. Zhu Q. Julien J.P. David S. Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J. Neurosci. 2002 22 15 6578 6586 10.1523/JNEUROSCI.22-15-06578.2002 12151537
172 Li Z.D. Li H. Kang S. Cui Y.G. Zheng H. Wang P. Han K. Yu P. Chang Y.Z. The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice. Cell Death Dis. 2022 13 11 1006 10.1038/s41419-022-05459-4 36443285
173 Han F. Xiao B. Wen L. Loss of glial cells of the hippocampus in a rat model of post-traumatic stress disorder. Neurochem. Res. 2015 40 5 942 951 10.1007/s11064-015-1549-6 25749890
174 Imbe H. Kimura A. Donishi T. Kaneoke Y. Chronic restraint stress decreases glial fibrillary acidic protein and glutamate transporter in the periaqueductal gray matter. Neuroscience 2012 223 209 218 10.1016/j.neuroscience.2012.08.007 22890077
175 Saur L. Baptista P.P.A. Bagatini P.B. Neves L.T. de Oliveira R.M. Vaz S.P. Ferreira K. Machado S.A. Mestriner R.G. Xavier L.L. Experimental post-traumatic stress disorder decreases astrocyte density and changes astrocytic polarity in the CA1 hippocampus of male rats. Neurochem. Res. 2016 41 4 892 904 10.1007/s11064-015-1770-3 26577396
176 Wang J. Gao F. Cui S. Yang S. Gao F. Wang X. Zhu G. Utility of 7,8-dihydroxyflavone in preventing astrocytic and synaptic deficits in the hippocampus elicited by PTSD. Pharmacol. Res. 2022 176 106079 10.1016/j.phrs.2022.106079 35026406
177 Kitayama N. Vaccarino V. Kutner M. Weiss P. Bremner J.D. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: A meta-analysis. J. Affect. Disord. 2005 88 1 79 86 10.1016/j.jad.2005.05.014 16033700
178 Gilbertson M.W. Shenton M.E. Ciszewski A. Kasai K. Lasko N.B. Orr S.P. Pitman R.K. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat. Neurosci. 2002 5 11 1242 1247 10.1038/nn958 12379862
179 Perez-Urrutia N. Mendoza C. Alvarez-Ricartes N. Oliveros-Matus P. Echeverria F. Grizzell J.A. Barreto G.E. Iarkov A. Echeverria V. Intranasal cotinine improves memory, and reduces depressive-like behavior, and GFAP + cells loss induced by restraint stress in mice. Exp. Neurol. 2017 295 211 221 10.1016/j.expneurol.2017.06.016 28625590
180 Wingo T.S. Gerasimov E.S. Liu Y. Duong D.M. Vattathil S.M. Lori A. Gockley J. Breen M.S. Maihofer A.X. Nievergelt C.M. Koenen K.C. Levey D.F. Gelernter J. Stein M.B. Ressler K.J. Bennett D.A. Levey A.I. Seyfried N.T. Wingo A.P. Integrating human brain proteomes with genome-wide association data implicates novel proteins in post-traumatic stress disorder. Mol. Psychiatry 2022 27 7 3075 3084 10.1038/s41380-022-01544-4 35449297
181 Gao F. Wang J. Yang S. Ji M. Zhu G. Fear extinction induced by activation of PKA ameliorates anxiety-like behavior in PTSD mice. Neuropharmacology 2023 222 109306 10.1016/j.neuropharm.2022.109306 36341808
182 Ji M. Zhang Z. Gao F. Yang S. Wang J. Wang X. Zhu G. Curculigoside rescues hippocampal synaptic deficits elicited by PTSD through activating CAMP‐PKA signaling. Phytother. Res. 2023 37 2 759 773 10.1002/ptr.7658 36200803
183 Yang S. Qu Y. Wang J. Gao F. Ji M. Xie P. Zhu A. Tan B. Wang X. Zhu G. Anshen Dingzhi prescription in the treatment of PTSD in mice: Investigation of the underlying mechanism from the perspective of hippocampal synaptic function. Phytomedicine 2022 101 154139 10.1016/j.phymed.2022.154139 35523115
184 Oliveros-Matus P. Perez-Urrutia N. Alvarez-Ricartes N. Echeverria F. Barreto G.E. Elliott J. Iarkov A. Echeverria V. Cotinine enhances fear extinction and astrocyte survival by mechanisms involving the nicotinic acetylcholine receptors signaling. Front. Pharmacol. 2020 11 303 10.3389/fphar.2020.00303 32300297
185 Ohno Y. Astrocytic Kir4.1 potassium channels as a novel therapeutic target for epilepsy and mood disorders. Neural Regen. Res. 2018 13 4 651 652 10.4103/1673-5374.230355 29722316
186 Tong X. Ao Y. Faas G.C. Nwaobi S.E. Xu J. Haustein M.D. Anderson M.A. Mody I. Olsen M.L. Sofroniew M.V. Khakh B.S. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat. Neurosci. 2014 17 5 694 703 10.1038/nn.3691 24686787
187 Zhang Z. Song Z. Shen F. Xie P. Wang J. Zhu A. Zhu G. Ginsenoside Rg1 prevents PTSD-like behaviors in mice through promoting synaptic proteins, reducing kir4.1 and TNF-α in the hippocampus. Mol. Neurobiol. 2021 58 4 1550 1563 10.1007/s12035-020-02213-9 33215390
188 Zhao M. Li D. Shimazu K. Zhou Y.X. Lu B. Deng C.X. Fibroblast growth factor receptor-1 is required for long-term potentiation, memory consolidation, and neurogenesis. Biol. Psychiatry 2007 62 5 381 390 10.1016/j.biopsych.2006.10.019 17239352
189 Xia L. Zhai M. Wang L. Miao D. Zhu X. Wang W. FGF2 blocks PTSD symptoms via an astrocyte-based mechanism. Behav. Brain Res. 2013 256 472 480 10.1016/j.bbr.2013.08.048 24013012
190 Feng D. Guo B. Liu G. Wang B. Wang W. Gao G. Qin H. Wu S. FGF2 alleviates PTSD symptoms in rats by restoring GLAST function in astrocytes via the JAK/STAT pathway. Eur. Neuropsychopharmacol. 2015 25 8 1287 1299 10.1016/j.euroneuro.2015.04.020 25979764
191 Wang J. Holt L.M. Huang H.H. Sesack S.R. Nestler E.J. Dong Y. Astrocytes in cocaine addiction and beyond. Mol. Psychiatry 2022 27 1 652 668 10.1038/s41380-021-01080-7 33837268
192 Ma R. Kutchy N.A. Hu G. Astrocyte-derived extracellular vesicle-mediated activation of primary ciliary signaling contributes to the development of morphine tolerance. Biol. Psychiatry 2021 90 8 575 585 10.1016/j.biopsych.2021.06.009 34417054
193 Canedo T. Portugal C.C. Socodato R. Almeida T.O. Terceiro A.F. Bravo J. Silva A.I. Magalhães J.D. Guerra-Gomes S. Oliveira J.F. Sousa N. Magalhães A. Relvas J.B. Summavielle T. Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine. Neuropsychopharmacology 2021 46 13 2358 2370 10.1038/s41386-021-01139-7 34400780
194 Jouroukhin Y. Zhu X. Shevelkin A.V. Hasegawa Y. Abazyan B. Saito A. Pevsner J. Kamiya A. Pletnikov M.V. Adolescent Δ9-tetrahydrocannabinol exposure and astrocyte-specific genetic vulnerability converge on nuclear factor-κB–cyclooxygenase-2 signaling to impair memory in adulthood. Biol. Psychiatry 2019 85 11 891 903 10.1016/j.biopsych.2018.07.024 30219209
195 Shelkar G.P. Gandhi P.J. Liu J. Dravid S.M. Cocaine preference and neuroadaptations are maintained by astrocytic NMDA receptors in the nucleus accumbens. Sci. Adv. 2022 8 29 eabo6574 10.1126/sciadv.abo6574 35867797
196 Boury-Jamot B. Carrard A. Martin J.L. Halfon O. Magistretti P.J. Boutrel B. Disrupting astrocyte–neuron lactate transfer persistently reduces conditioned responses to cocaine. Mol. Psychiatry 2016 21 8 1070 1076 10.1038/mp.2015.157 26503760
197 Shi P. Li Z. He T. Li N. Xu X. Yu P. Lu X. Nie J. Liu D. Cai Q. Guan Y. Ge F. Wang J. Guan X. Astrocyte‐selective STAT3 knockdown rescues methamphetamine withdrawal‐disrupted spatial memory in mice via restoring the astrocytic capacity of glutamate clearance in DCA1. Glia 2021 69 10 2404 2418 10.1002/glia.24046 34110044
198 Molofsky A.V. Kelley K.W. Tsai H.H. Redmond S.A. Chang S.M. Madireddy L. Chan J.R. Baranzini S.E. Ullian E.M. Rowitch D.H. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 2014 509 7499 189 194 10.1038/nature13161 24776795
199 Blanco-Suarez E. Liu T.F. Kopelevich A. Allen N.J. Astrocyte-secreted chordin-like 1 drives synapse maturation and limits plasticity by increasing synaptic glua2 ampa receptors. Neuron 2018 100 5 1116 1132.e13 10.1016/j.neuron.2018.09.043 30344043
200 Nazari S. Amiri M. Faez K. Van Hulle M.M. Information transmitted from bioinspired neuron–astrocyte network improves cortical spiking network’s pattern recognition performance. IEEE Trans. Neural Netw. Learn. Syst. 2020 31 2 464 474 10.1109/TNNLS.2019.2905003 30990195
201 De Pittà M. Brunel N. Multiple forms of working memory emerge from synapse–astrocyte interactions in a neuron–glia network model. Proc. Natl. Acad. Sci. 2022 119 43 e2207912119 10.1073/pnas.2207912119 36256810
202 Becker S. Nold A. Tchumatchenko T. Modulation of working memory duration by synaptic and astrocytic mechanisms. PLOS Comput. Biol. 2022 18 10 e1010543 10.1371/journal.pcbi.1010543 36191056
203 Verdera H.C. Kuranda K. Mingozzi F. AAV vector immunogenicity in humans: A long journey to successful gene transfer. Mol. Ther. 2020 28 3 723 746 10.1016/j.ymthe.2019.12.010 31972133
204 Wang Q. Li W. Lei W. Chen G. Xiang Z. Xu L. Liu M. Lineage tracing of direct astrocyte-to-neuron conversion in the mouse cortex. Neural Regen. Res. 2021 16 4 750 756 10.4103/1673-5374.295925 33063738
205 Zhang Y. Li B. Cananzi S. Han C. Wang L.L. Zou Y. Fu Y.X. Hon G.C. Zhang C.L. A single factor elicits multilineage reprogramming of astrocytes in the adult mouse striatum. Proc. Natl. Acad. Sci. 2022 119 11 e2107339119 10.1073/pnas.2107339119 35254903
206 Guo Z. Zhang L. Wu Z. Chen Y. Wang F. Chen G. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell 2014 14 2 188 202 10.1016/j.stem.2013.12.001 24360883
