==== Front Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 33261169 10.3390/ijms21239039 ijms-21-09039 Review Rethinking Intellectual Disability from Neuro- to Astro-Pathology https://orcid.org/0000-0001-6451-1094Fernández-Blanco Álvaro 1 Dierssen Mara 123* 1 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; alvaro.fernandez@crg.eu 2 Universitat Pompeu Fabra (UPF), Dr. Aiguader 88, 08003 Barcelona, Spain 3 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain * Correspondence: mara.dierssen@crg.eu; Tel.: +34-933160140 27 11 2020 12 2020 21 23 903930 10 2020 25 11 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under neuronal control. However, this vision has recently evolved into a more integrative conception in which astroglia, rather than just acting as metabolic supply and structural anchoring for neurons, interact at distinct levels modulating neuronal communication and possibly also cognitive processes. Recently, genetic tools have made it possible to specifically manipulate astrocyte activity unraveling novel functions that involve astrocytes in memory function in the healthy brain. However, astrocyte manipulation has also underscored potential mechanisms by which dysfunctional astrocytes could contribute to memory deficits in several neurodevelopmental disorders revealing new pathogenic mechanisms in intellectual disability. Here, we review the current knowledge about astrocyte dysfunction that might contribute to learning and memory impairment in neurodevelopmental disorders, with special focus on Fragile X syndrome and Down syndrome. astrocytesneurodevelopmental disordersmemory deficitsFragile X syndromeDown syndrome ==== Body 1. Introduction Neurodevelopmental disorders are multifaceted conditions characterized by different degrees of intellectual disability and impairment in communication (verbal and non-verbal) and motor skills, among others. Intellectual disability is defined by an overall intelligence quotient below average and deficits in adaptive behaviors, with an early onset during childhood [1,2]. These disorders arise from genetic alterations and/or environmental factors that influence how the brain develops and have short and long-term consequences on cognition, social interaction, and behavior. Traditionally, neurodevelopmental disorders such as Down syndrome (DS), Fragile X syndrome (FXS), or Rett syndrome have been considered as synaptopathies [3,4,5], characterized by neuronal alterations important for learning and memory, including abnormalities in dendritic architecture [6,7], with changes in the complexity of dendritic arborizations [7], and in spine number [6,7,8,9,10,11,12], shape and length [7,10,13], reflecting more immature spines [10,14]. These changes are accompanied by impaired synaptogenesis [15,16,17], alterations in synaptic transmission and broad deficits in synaptic plasticity [18,19,20,21], as revealed by mouse models for these syndromes. Synaptic plasticity and, specifically, changes in the strength of synaptic connectivity of neurons that are activated at the time of learning are thought to be the basis of memory formation [22,23]. However, the alteration of the neuronal component does not completely explain the synaptic alterations and neurophysiological changes nor the behavioral and memory deficits observed in these neurodevelopmental disorders. This is possibly the reason why strategies that focused on restoring neuronal dendritic abnormalities, impaired synaptic plasticity, and different imbalances in neurotransmission only showed partial recoveries in the memory deficits associated with intellectual disability both in mouse models [9,24] and in humans [24,25,26]. Thus, we need to consider alternative mechanisms that may contribute to memory pathology. Lately, the discovery of unique astroglial features that include roles in synaptic plasticity and memory function has broadened and refurbished the conception of brain function in health and disease. Recent reports underscoring the astrocyte capability to modulate neuronal circuit activity and to potentiate synapses [27,28] have led to consider that astrocytes are both necessary [29,30,31] and sufficient [28] for memory function. Moreover, studies on intellectual disabilities have recently uncovered potential contributions of astrocytes to their pathophysiology [16,32,33,34]. In fact, increasing body of evidence suggests that changes in astrocyte physiology and morphology might be involved in Alzheimer’s disease, FXS, or DS, among others [35,36,37,38,39]. In these pathological conditions, astrocytes modify their function and exhibit some common pathological features including an increase in the number and size of astrocytes together with increased expression of astroglial proteins such as S100 calcium-binding protein β (S100β) [40,41,42,43], a calcium binding protein coded by a HSA21 gene, and the glial fibrillary acidic protein GFAP [36,43,44,45], the main intermediate filament proteins of mature astrocytes. In fact, these pathophysiological changes in astrocytes have been linked with reduced neuronal activity [41], spine defects [14,32,34], and impaired memory performance [33,46,47,48]. In this review, we present the currently available data that state the involvement of astrocytes in synaptic transmission and in memory function both in the healthy and in the diseased brain. Given the emerging role of astrocytes in synaptic transmission, we propose specific mechanisms that may explain astrocyte dysfunction in neurodevelopmental disorders and can contribute, at least to some extent, to the memory deficits associated with these brain disorders. Specifically, we describe the main astroglial alterations in FXS and DS and propose new lines of research that may help to better understand the role of astrocytes in memory dysfunction. 2. Astrocyte Function in the Healthy Brain Astrocytes are star-shaped cells whose function has been classically restricted to maintain brain homeostasis and to support neurons from a metabolic and structural perspective. Beyond these classical functions, astrocytes also play a role in synaptic physiology due to the expression of an extensive number of functional neurotransmitter receptors that allow them to sense different types of neurotransmitters [49,50]. Astrocytes are also able to release several neurotransmitters and neuromodulators, such as glutamate, GABA, ATP/adenosine and D-serine, to the synaptic cleft [51,52], through intracellular calcium concentration changes, so-called calcium oscillations [27,53,54]. This process, termed gliotransmission, has been extensively studied, as it influences synaptic physiology and potentiates or depresses synapses both in the short and long-term [27,28,55]. For this reason, it is widely accepted that astrocytes are an integral component of the synapse (tripartite synapse [56]) that, hand in hand with neurons, shape the synaptic transmission in the brain. However, the mechanisms by which astrocytes mediate these structural and functional responses have been a subject of intense debate [52,57,58]. Perisynaptic astrocytic processes (PAPs) containing neurotransmitter receptors embrace the synaptic cleft, isolating synapses in the tridimensional space. Taking into consideration that those fine astrocyte processes are covering around 60% of postsynaptic dendritic spines in the mature hippocampus [59], and that a single astrocyte can enwrap from 10,000 to 100,000 synapses [60], their potential to influence and shape synaptic transmission is gigantic. In addition, PAPs are remarkably dynamic, being as plastic as their neuronal counterparts due to their capability to change morphology, volume, and motility in response to specific neuronal activity patterns within minutes [61,62,63]. This astrocyte–synapse interplay is fundamental for neural transmission but also for other important processes related to cognitive function, such as spine maturation [62,64,65] and structural and functional synaptic plasticity by means of secreted molecules, such as thrombospondins [32,34,66], or by direct physical contact with synapses [62]. In fact, dendritic protrusions that are in contact with PAPs are typically more mature and stable than those present in the “bipartite synapses” [62]. 3. Astrocyte Involvement in Learning and Memory in the Healthy Brain The dynamic nature of astrocyte–synapse interactions is believed to sculpt and shape neuronal networks not only during neurodevelopment but also in adult stages. The prominent astroglial role in synaptic physiology suggests an astroglial involvement in memory function. Animal studies focused on functional neuron–astrocyte cross-talk have unraveled that the bidirectional communication between neurons and astrocytes is important for neuronal plasticity [28,31] and, more specifically, for memory function [28,29,30,31]. Recently, genetic tools such as chemogenetics and optogenetics have made it possible to specifically manipulate astrocytes in the brain, which may help understanding how astrocyte dysfunction may negatively impact memory function in neurodevelopmental disorders. One of the first evidences supporting astrocytes involvement in memory processes came from transgenic mice overexpressing S100β [48]. Specifically, upregulation of S100β mRNA and protein levels in astrocytes led to impaired long-term potentiation (LTP) and exacerbated long-term depression (LTD) in hippocampal pyramidal neurons. These alterations in neuronal physiology were accompanied by a significant impairment in performance of the Morris water maze navigation test, a hippocampal-dependent task. Conversely, S100β-null mice showed enhanced LTP accompanied by enhanced spatial memory in the Morris water maze test and in contextual fear-conditioning [67]. Interestingly, exogenous application of S100β reversed the enhanced LTP of S100β-null mice, suggesting that astrocyte-secreted S100β can also influence neuronal activity. In fact, S100β has Ca2+ binding properties that reduce extracellular Ca2+ concentration and affect the neuronal firing pattern [68]. S100β also influences neuronal excitability since intracellular upregulation of S100β protein concentration increases astrocyte calcium oscillations and has been related with reduced neuronal excitability [41]. Indeed, the effects of S100β are concentration-dependent: while low concentrations have protective brain effects and promote the development and maturation of the central nervous system [69], high S100β concentrations are toxic, promote proinflammatory responses [70], and have detrimental consequences for neurons that include apoptotic cell death [71]. More recent studies that manipulated astroglial activity in a more mechanistic and time-constrained manner have demonstrated the astrocyte involvement in memory function [28,29,30,31]. For example, transgenic mice that allowed the selective expression of tetanus toxin (TeNTΔ1) in astrocytes resulted in the abolishment of the Ca2+ dependent neurotransmitter release and impaired, in vivo, the gamma oscillations in the hippocampus [30]. This fact has far-reaching implications since gamma rhythms are related with several cognitive processes such as attention, learning, and different types of memory [72]. Remarkably, the temporal blockade of astrocyte vesicular release by TeNT expression resulted in impaired recognition memory, while restoring the astrocyte capability to release gliotransmitters rescued these memory deficits. This study elegantly demonstrated in a very mechanistic manner that gliotransmission is necessary for particular types of memory and placed the astrocyte as a sophisticated and intricate player in memory function. However, it also left several open questions: How do astrocytes participate in learning? Can astrocytes play a role in the acquisition, consolidation, storage, and recall of memories? Part of these questions were answered in a recent study in which astrocytes were selectively activated in the CA1 region of the hippocampus during memory acquisition, either by chemogenetics (GFAP-hM3Dq) or by optogenetics (GFAP-OptoGq) before (but not after) learning [28]. Astrocyte activation before learning resulted in memory enhancement of fear conditioning that was accompanied by an increase in the recruitment of active neurons during memory acquisition. This would suggest that more neurons support this particular memory in this particular brain region. Despite this study suggests that astrocyte activation might be important for memory acquisition, it does not prove whether astrocytes are activated in physiological conditions in the brain during memory operations. Other studies specifically abolished astrocyte activity and/or signaling. For example, pharmacological inhibition of L-lactate production in astrocytes prevented long-term potentiation of CA3-CA1 synapses, in vivo, and impaired long-term episodic memory [31]. L-lactate is produced by astrocytes, and its transport from astrocytes to neurons is important for neuronal metabolism. This study suggests that astrocyte-neuron lactate transport is involved in long-term memory formation and for late-LTP. Another study that specifically activated the Gi pathway in astrocytes before learning, impaired remote (yet not the recent) memory recall [29]. G protein-coupled receptors play key roles in intercellular signaling in the brain [73]. While they inhibit neuronal activity, their effects are opposite in astrocytes, rising intracellular Ca2+ levels and promoting glutamate release [74]. Since recent-to-remote memory transition depends on the activation and recruitment of cortical regions such as the anterior cingulate cortex (ACC) [75,76,77], the authors activated the Gi pathway in CA1 astrocytes by GFAP-hM4Di designer receptor [29]. Interestingly, even though both CA1 and the ACC are important for recent and remote memories, Gi pathway activation in astrocytes by clozapine N-oxide, an hM4Di agonist, prevented neuronal activation (assessed by c-Fos expression) in the ACC but not in CA1. This suggests that astrocytes would modulate the functional connectivity between neurons in a projection-specific manner. As such, CA1 astrocytes would distinguish between distinct CA1 pyramidal neurons according to their projection target and would distinctively modulate their activity. It is noteworthy to mention that the manipulation (either activation [28] or inactivation [29]) of astrocyte activity with designer drugs itself, did not interfere with memory recall suggesting that astrocyte activity is necessary during memory acquisition but not for recent or remote memory recall. In view of the recent discoveries involving astrocytes in memory function, one would consider that astrocyte dysfunction in any cognitive disorder might interfere with learning and memory. In the following section, we have selected the most relevant mechanisms by which astrocytes could impact and contribute to memory deficits in neurodevelopmental disorders, focusing on FXS and DS. 4. Astrocyte Dysfunction in Neurodevelopmental Disorders The involvement of astroglia in the pathophysiology of several cognitive disorders is supported by evidence that report that numerous glial genes are misregulated in neurodevelopmental disorders [40,78]. The proteins encoded by these genes play important roles in the brain, including their involvement in cell cycle progression, neuronal differentiation, and repairing the neuronal damage. Together with these genetic alterations, astrocytes also display aberrant morphology [42,79] and physiology [41] that have been directly shown to contribute not only to synaptic defects and changes in neuronal excitability [41] but also to neuronal survival [80,81]. It is frequent to detect different degrees of astrocyte reactivity (or astrogliosis) in many brain disorders [36,42,79]. The term astrogliosis refers to changes at the molecular, cellular, and functional level that appear as a response to brain damage or in genetic brain disorders [82]. The changes in astroglial function vary depending on the severity of the lesion or the genetic alteration and have repercussions on adjacent neurons. In general, astrogliosis involves morphological and physiological alterations, such as an increase in the number and size of the astrocytes, and changes in the expression of astroglial proteins (GFAP and S100β) [82]. Astrogliosis promotes, together with peripheral macrophages and microglia, an adaptive state that helps facing the origin of the brain insult (infection, hemorrhage, genetic disturbance, etc.) by phagocytizing external factors, eliminating toxic neuronal debris, and/or promoting neuronal survival [82,83,84]. However, in cognitive disorders such as DS, FXS, or Alzheimer’s disease, astrocytes are in a chronic “reactive state” (or abnormal astrogliosis), a continuous dysfunctional mode that can be maladaptive and contribute to the progression of neurodegeneration of these brain disorders [42,85]. Given the role of astrocytes in the regulation of synaptic function, it is not surprising that changes in astrocyte activity, protein secretion, deregulation in gene expression, or modification in the astroglial membrane channel composition that occur in neurodevelopmental disorders might impair synaptic transmission and, therefore, memory function. In the next section, we review some of the most relevant studies demonstrating that astrocytes are involved in the synaptic pathology in DS and FXS, the two most common genetic forms of intellectual disability. 4.1. Astrocyte Pathology in Fragile X Syndrome (FXS) FXS is a genetic condition caused by an expansion of the CGG triplet within the fragile X mental retardation 1 gene (FMR1) that leads to its transcriptional silencing. FMR1 is located in the X chromosome and encodes for the mRNA binding protein Fragile X Mental Retardation Protein 1 (FMRP) that regulates protein synthesis. The absence of FMRP interferes with brain development and contributes to FXS pathophysiology [86,87]. Several lines of evidence suggest that astroglia might also contribute to synaptic function impairment and memory deficits of individuals with FXS [16,32,33]. However, studies on astrocyte pathology in FXS are sparse and inconsistent: one group reports no astrogliosis seen in post-mortem brains of persons with FXS [88] while other describes a gliosis in the CA4 hippocampal region of two postmortem FXS brains [89]. One of the most commonly used mouse models for the study of FXS is the Fmr1 knock-out (KO) that recapitulates most of the neuronal alterations and the phenotypical traits of FXS [90]. This model lacks the expression of FMRP protein in neurons and astrocytes being thus an interesting tool to uncover the role of astrocyte in FXS. It is still unclear, however, whether FMRP protein has similar or different functions when expressed in neurons or in astrocytes. In FXS, the FMRP protein regulates metabotropic glutamate receptor 5 (mGluR5) expression in astrocytes, but not in neurons. In Fmr1 KO astrocytes, the absence of FMRP leads to a downregulation of mGluR5 that leads to reduced expression of glutamate transporter 1 (GLT-1) and, subsequently, to decreased glutamate uptake in astrocytes [91] (Figure 1). Increased mGluR5 signaling has been long proposed to account for the syndromic features and the cognitive deficits in FXS [92,93]. In fact, the acute and chronic pharmacological inhibition of mGluR5 in adult Fmr1 KO mice restores dendritic alterations including aberrant dendritic morphology, increases protein synthesis, and rescues memory deficits associated with FXS [94,95]. As mentioned, mGluR5 is upregulated in neurons [96] but downregulated in astrocytes [91]. Thus, the contribution of mGluR5 dysregulation to FXS pathophysiology is more complex than expected. mGluR5 activation has been associated with a form of synaptic depression, called mGluR5-mediated LTD resulting from the internalization of surface-expressed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as a response to mGluR5 activation in neurons [97,98]. This is accompanied by reduced presynaptic release of glutamate [99] that, overall, leads to an exaggerated LTD in Fmr1 KO mice [100]. Conversely, mGluR5 downregulation in Fmr1 KO astrocytes has been associated with lower astroglial GLT-1 levels [91]. This might contribute to reduced glutamate reuptake and, therefore, to increased extracellular glutamate levels which subsequently might activate mGluR5 receptors in postsynaptic neurons, thus promoting mGluR5-mediated LTD. Interestingly, increased GFAP expression, a marker of astrocyte activation, has been reported in the cortex, hippocampus, and striatum of Fmr1 KO mice [101], suggesting a reactive gliosis in these particular brain regions. In general, increased GFAP expression is accompanied by an increase in the number of astrocytes [82]. Nevertheless, there is only one description of persistent astrogliosis (increased GFAP and S100β expression) in the cerebellum of Fmr1 KO mice [102], but no systematic quantification of the astroglial number has been performed in FXS. Complementary to these data, astrocyte physiology was also reported to be altered in a mouse model with a gain-of-function of the premutation CGG (preCGG) repeat within the FMR1 gene. preCGG knock-in mice showed increased and asynchronous calcium activity that was explained by increased glutamate levels in the extracellular space due to reduced expression of glutamate transporters such as the glutamate-aspartate transporter 1 (GLAST-1) and GLT-1 in astrocytes [103]. In cellular FXS models, control hippocampal neurons grown in co-culture with FXS astrocytes, showed aberrant dendritic morphology and decreased expression of synaptic markers (PSD-95) [103]. Conversely, when co-cultured with control astrocytes, hippocampal FXS neurons developed normally. These dendritic alterations were explained by a reduction in the expression of thrombospondin (TSP-1) in Fmr1 KO mice astrocytes [32]. TSP-1 is synthesized and secreted by astrocytes [104], promoting synaptogenesis [66] and neurite outgrowth [105] both during the neurodevelopment [106] and in the adult brain [107]. Interestingly, both culturing Fmr1 KO hippocampal neurons with astrocyte-conditioned media of FMRP-expressing (control) astrocytes and the exogenous application of TSP-1, prevented dendritic spine defects in Fmr1 KO neurons. This indicates that astrocyte-secreted TSP-1 is a potent modulator of dendritic morphology and that reduced TSP-1 in FXS astrocytes would contribute to dendritic alterations in FXS neurons. In agreement with these results, an astrocyte-specific Fmr1 KO mouse model shows similar dendritic and cognitive alterations than Fmr1 KO mice [33]. However, restoring FMRP expression specifically in Fmr1 KO astrocytes was not sufficient to restore dendritic and learning deficits associated with FXS suggesting that astrocyte dysfunction does not completely account for FXS pathophysiology. 4.2. Astrocyte Pathology in Down Syndrome DS is the most prevalent cause of intellectual disability of genetic origin. It is due to the presence of a third copy of HSA21, which results in deregulated gene expression leading to altered brain function. DS brain manifestations include changes in the volume and connectivity of certain brain regions such as the cerebral cortex, cerebellum, and hippocampus [108,109], and neuroarchitectural alterations such as spine dysgenesis [14,110], decreased spine density [8,9], and dendritic atrophy [7]. These alterations may deeply perturb information processing in structures related to cognitive functions such as hippocampus and cortex [110] and are assumed to underlie some cognitive impairments in DS, ranging from learning difficulties to spatial memory deficits [111]. In DS, there is an increased number of astrocytes [42,85,112] (Figure 2). In post-mortem brains of individuals with DS, astrocytes are more abundant, bigger, and express more astroglial markers (S100β, GFAP) than age-matched controls [42,112]. Similar observations were reported in Ts65Dn, a partial trisomic mouse model for DS [113]. Nevertheless, there are some discrepancies that suggest that GFAP is reduced in particular brain areas [114,115]. DS fetuses have a higher percentage of cells with astrocytic phenotype in the hippocampus [116], thus indicating a shift from neurogenesis to gliogenesis. This neurogenic-to-gliogenic switch was confirmed in induced pluripotent stem cells (iPSCs) from monozygotic twins discordant for trisomy 21 in which a shift towards the astroglial phenotype was detected in the transcriptional signature of DS-iPSC-derived cells, as shown by the increased expression of GFAP, S100β, and Vimentin [117]. HSA21 genes, such as the Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), may play a role through the activation of the astrogliogenic transcription factor signal transducer and activator of transcription (STAT) that subsequently induces precocious astrogliogenesis by switching the neural progenitor fate towards the astroglial phenotype [118]. These findings suggest that gene expression deregulation in DS, and specifically changes in the DYRK1A-STAT signaling pathway, control the onset of the gliogenic switch and favor the neural progenitor cell fate towards astrogliogenesis. The increased astrocyte number [42,85,112] is accompanied by a reduction in the neuronal population [116,119], due to impaired proliferation [116,120] and increased apoptosis [116,121]. This implies that the neuron to glia ratio would be reduced in DS, which could have profound implications. In fact, astrocytes are distributed in non-overlapping synaptic territories in the tridimensional space, which allows to modulate the synaptic transmission of several neurons at a time. These separated anatomical domains, called synaptic islands [122], are particularly relevant, as they might prevent the redundancy of different astrocytes controlling the same or neighboring synapses. In the DS scenario, astrocytes are increased both in number and in volume while neuronal numbers are reduced. These physical changes may not only affect how neurons and astrocytes are distributed and positioned in the tridimensional space but would also determine how many neurons a single astrocyte contacts. As a consequence, the astrocyte-associated area of influence would be affected, with probable consequences on neuronal communication. We speculate that the changes in the tridimensional arrangement could lead to a synaptic island overlap, promoting a misregulation and redundancy in the astroglial control of synaptic transmission. In DS, astrocytosis is maintained throughout life and is accompanied by an immature astroglial phenotype with decreased interlaminar processes [123]. Moreover, astroglial physiology is altered, as shown by the increased spontaneous calcium oscillations in DS astrocytes [41]. This may impact neuronal function, since intracellular calcium transients in astrocytes induce the release of gliotransmitters. In fact, DS-iPSCs-derived astrocytes exhibited increased calcium activity, which was shown to subsequently reduce the excitability of co-cultured neurons [41]. The increase of calcium oscillations was attributed to S100β overexpression, since normalization of S100β expression restored calcium activity to control levels [41]. Interestingly, the reduction of evoked field potentials in DS iPSCs co-cultured neurons was prevented by blocking the A1 adenosine receptor (A1R) with 8-Cyclopentyl-1,3-dipropyl xanthine (DPCPX, a potent A1R antagonist). This would suggest that either A1R is overexpressed in neurons—a fact that to the best of our knowledge has not yet been described. A second possible explanation would be that increased adenosine concentration driven by the hydrolysis of an excess of ATP released consequent to the astrocyte hyperactivity would activate neuronal A1Rs. Adenosine has been shown to activate A1R in neighboring synapses [124,125] and A1R activation inhibits glutamate release [126,127], consistent with the reduced glutamate levels in DS that lead to an excitatory/inhibitory imbalance [128,129,130]. Specifically, the levels of glutamate are reduced in several brain regions including the parahippocampal gyrus [128] in the hippocampus [129] and in peripheral tissues [130], which could produce an overall reduction in the neuronal activity. These reduced glutamate levels could also be explained by the increased expression of the glutamate transporter GLAST-1 in DS astrocytes leading to a higher glutamate uptake compared to control astroglia [131]. Conversely, the levels of GLT-1 were preserved in DS astrocytes. Although there is still some controversy, it seems that in DS, there is also an increased inhibition [132,133,134], since blocking GABAA receptors restores LTP deficits in Ts65Dn mice [135], while excitation is preserved [132] or slightly reduced [136]. Some studies suggested that the number of excitatory synapses would be reduced [136], while inhibitory synapses would be preserved [136]. In DS, there is an upregulation of mGluR5 both in fetal and adult DS brains [137] and this mGluR5 upregulation is astrocyte-specific [137]. However, no mechanistic studies associating mGluR5 with synaptic alterations either at the structural or functional level have been performed in mouse models for DS. Nevertheless, the deregulation of mGluR5 signaling in neurons and/or astrocytes can ultimately lead to alterations in the astrocyte–synapse cross-talk that is essential for synaptic transmission and contribute, at least to some extent, to the memory deficits associated with DS. Interestingly, and similar to the FXS scenario, the co-culture of rat hippocampal neurons that were grown on top of human DS astrocytes showed reduced levels of TSP-1 (around 60% lower compared to WT astrocytes) which led to a reduction in the neuron spine number and more immature (filopodia) spines compared to neurons cultured with control astrocytes [14,34]. Conversely, the addition of TSP-1 in co-cultures of neurons and DS astrocytes restored the alterations in the dendritic spines, suggesting that TSP-1 dysfunction in DS contributes to aberrant dendritic morphology. Studies focusing on astrocyte pathology on DS are scarce and limited and very few have explored in detail the mechanisms by which astrocytes could contribute to synaptic alterations in DS. Thus, exploring the mechanisms that might lead to astrocyte–synapse communication such as mGluR5 signaling, purinergic transmission, or deficits in TSP-1 secretion can provide new levels of understanding about the contribution of astrocyte dysfunction to memory deficits in DS. 5. Astrocytic Phenotypes in DS and FXS: Same Players for Different Phenotypes? Neurodevelopmental disorders are among the most complex medical conditions, in terms of pathophysiological mechanisms and possible treatments. Most of them lead to intellectual disability, including both cognitive and behavioral impairments that have been traditionally ascribed to neuronal defects. In the last 20 years, astrocytes have emerged as key players in neurotransmission, helping to address longstanding questions in the intellectual disability field with an entirely novel perspective. Astrocytes also hold great promises for cognitive and behavioral repair. Given that FXS and DS are the most preeminent neurodevelopmental disorders associated with intellectual disability, we have centered our review in those disorders, and on the astrocyte alterations that may impair fundamental mechanisms required for memory function including neuronal communication and synaptic function. Interestingly, we found several studies in FXS and in DS indicating that these disorders share deficits in astrocyte structure, gene expression, and/or function. How those may contribute to the different intellectual disability profiles in FXS and DS is still unexplored, as are also other mechanisms by which astrocytes could contribute to memory deficits. Interestingly, while there is a lifelong astrocytosis in DS [85], this phenotype is not detected in FXS. One of the most important but also mysterious features of the astrocyte–neuron communication is the existence of so-called synaptic islands. Between 50% and 60% of hippocampal synapses are engulfed by extensive astrocytic ensheathment that prevents spillover and spatially isolates individual synapses from each other and from the extra-synaptic space [59,122]. However, the study of these non-overlapping astroglial domains have not been explored neither in FXS nor in DS. This is particularly relevant because it can provide new levels of understanding about how neurons and astrocytes interact in the tridimensional space and how astrocyte–synapse cross-talk varies over time. In the DS scenario, the decreased neuron to astrocyte ratio would imply that the astroglial domains would be disturbed. The increased number and volume of astrocytes would lead either to smaller astroglial domains or to overlapping synaptic islands and, therefore, the boundaries between astroglial domains would be more diffuse. However, due to the dynamic nature of astrocytes, which are remarkably motile and can engage and disengage from synapses spontaneously or in response to physiological (or pathological) stimuli [61,62,63], these synaptic islands are expected to change over time. Thus, even though no substantial changes in astrocyte number or volume have been described in FXS that might indicate changes in the neuron to astrocyte ratio, it could happen that the dynamics of the extensive astrocytes processes in FXS might vary, thus changing the defined astroglial locations in which astrocytes modulate a specific number of synapses. Likewise, this hypothetical shift in the motility of the astroglial domains might also produce that the well-established boundaries between synaptic islands become more diffuse, as in DS, leading to dysregulation of synaptic transmission in FXS. In both DS and FXS, even though no direct conclusions can be extracted, one would expect that synaptic transmission would be affected somehow, probably by adding some redundancy in the system since more astrocytes would be in charge of controlling a similar number of synapses or because the different astroglial topology would modify the synaptic astroglial coverage that is important for synaptic transmission. Furthermore, the scope of the astroglial contribution to synaptic alterations in neurodevelopmental disorders also includes other important players such as proteins related with the neurotransmitter and ionic homeostasis such as glutamate transporters (GLT-1 and GLAST-1), glutamine synthetase, aquaporins, potassium channels, and lactate transporters. How specific alterations in these proteins might contribute to memory deficits in FXS and DS might include changes in neuron excitability due to impaired astrocyte–synapse cross-talk. The study of these alterations can provide invaluable clues to comprehend the molecular basis of intellectual disability in these brain disorders. For example, differences in glutamate transporters such as GLT-1 and GLAST-1 modifies the glutamate levels [91] that influence neuronal activity. In FXS, reduced GLT-1 and GLAST-1 increase glutamate levels [91,103] lead possibly to a depression of the synaptic transmission by mGluR5-mediated LTD, or are causative, at least to some extent, for the hyperexcitability that has been widely described in FXS [138,139,140]. Conversely, in DS, GLAST-1 is overexpressed in astrocytes and leads to an increased astroglial glutamate uptake [131], which reduces the available glutamate in the extracellular space and probably reduces neuronal activity. As such, changes in the expression of several receptors such as mGluR5, which are downregulated in FXS astrocytes [91] and upregulated both in FXS neurons [96] and in DS astrocytes [141] can affect how neurons and astrocytes interact at the synaptic level. In neurons, mGluR5 is functionally coupled to N-methyl-D-aspartic acid receptors (NMDAR) by means of a protein scaffold constituted by Homer isoforms and Shank, among others [142,143]. In fact, mGluR5 activation has been shown to enhance NMDAR function [144,145] but also to promote mGluR5-dependent LTD [146], and these differences are probably due to different patterns of incoming glutamatergic signals in the postsynaptic neuron. Despite the well-known roles of mGluR5 in synaptic plasticity in neurons [147,148], very few studies have studied the contribution of astroglial mGluR5 signaling to the synaptic transmission either in FXS or in DS. Unraveling differential roles of mGluR5 in neurons and astrocytes in FXS would help to better dissect and elucidate the potential mechanistic interactions between neurons and astrocytes associated with mGluR5 dysfunction. Correspondingly, in DS, the investigation of mGluR5 function both in neurons and astrocytes would help to better understand the dysfunctional cross-talk in the tripartite synapse. In DS, mGluR5 is upregulated in astrocytes [141] (and probably in neurons [137]), yet no mechanistic studies have demonstrated the potential implications of mGluR5 dysfunction, neither in neurons nor in astrocytes. Other important contributors to the intellectual disability phenotype would involve impairments in spine maturation and synaptogenesis not only during neurodevelopment but also in adult stages, as seen by the TSP-1 downregulation also in FXS and in DS [14,32,34]. Taking into consideration that the formation of new synapses and the strengthening of the existing ones is indispensable for memory function [22,23], these astrocyte-driven dendritic deficits that hamper synaptic function might have profound implications for the establishment of specific connectivity maps that support memories over time both in FXS and DS. Thus, strategies targeting TSP-1 deficits both in FXS and in DS can provide new lines of investigation to tackle dendritic alterations that are believed to contribute to memory deficits associated with these brain disorders. Another interesting approach that could shed light into the astroglial contribution to memory deficits could be the restoration of epigenetic mechanisms that deregulate gene expression. For instance, in FXS hypermethylation of CGG triplets avoid FMRP expression in neurons [149,150]. In DS, there is a hypermethylation that represses gene expression in certain chromosomes [151,152,153] together with a hypoacetylation described in Ts65Dn hippocampus [154], a mouse model of DS, that would promote, in general, an downregulation of several memory-related genes. Recently, it has been possible to specifically edit the epigenetic footprints in a gene-specific manner. In fact, the demethylation of CGG repeats in iPSCs-derived FXS neurons induces an active chromatin state and restores most of the dendritic alterations to WT levels [150]. However, this approach has not been directed yet to restore genetic alterations due to epigenetic imbalance in the astroglial population. For instance, it could be interesting to restore GFAP and/or S100β expression in DS in which these genes are upregulated in order to see potential recoveries at the synaptic level and, possibly, also in cognition. 6. Astrocyte Involvement in Memory Pathology in Neurodevelopmental Disorders: A Look into the Future In conclusion, our review shows that, to date, only few studies have specifically targeted the astrocytes involved in the cognitive and behavioral deficits associated with intellectual disability. Nevertheless, all the alterations detected in FXS and DS at the synaptic level in which astrocytes are involved, suggest that their perturbation has a detrimental effect on these disorders, and we propose specific models that would explain these alterations in FXS and in DS. This is an exciting time for astrocyte research since we are beginning to understand unique and fascinating astroglial features that go beyond the outdated “neurocentric” vision. Shortly, and every time more frequently, we will hear about new discoveries that involve the astrocytes in different brain functions such as attention, sleep, executive functions, social behavior, and in several types of memory since we are now able to manipulate the astrocyte activity while mice undergo different tasks in a very time-constrained manner. However, more importantly, we may envisage that astrocytes could become a promising target for new treatments for a number of brain disorders. Acknowledgments We thank Miguel Sabariego, Cèsar Sierra, René Crans, and Juan Luís Musoles for their critical reading of the manuscript. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author Contributions Á.F.-B. and M.D. conceived the paper, Á.F.-B. performed the bibliographic research. All authors have read and agreed to the published version of the manuscript. Funding The lab of MD is supported by the CRG Severo Ochoa excellence grant, the CIBER of Rare Diseases and Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement de la Generalitat de Catalunya (Grups consolidats 2017 SGR 926). We also acknowledge the support of the Agencia Estatal de Investigación (PID2019-110755RB-I00/AEI/10.13039/501100011033), H2020 SC1 Gene overdosage and comorbidities during the early lifetime in Down Syndrome GO-DS21- 848077, Jerôme Lejeune Foundation, NIH (Grant Number: 1R01EB 028159-01), Marató TV3, JPND Heroes project, and the Spanish Ministry of Science and Innovation (MICINN)to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. Conflicts of Interest The authors declare no conflict of interest. Abbreviations DS Down syndrome FXS Fragile X syndrome S100β S100 calcium-binding protein β HSA21 Homo Sapiens Autosome 21 GFAP Glial Fibrillary Acidic Protein GABA Gamma aminobutyric acid ATP Adenosine triphosphate PAP Perisynaptic astrocytic process LTP Long-term potentiation LTD Long-term depression TeNT Tetanus Neurotoxin hM3Dq human Gq-coupled M3 muscarinic receptor CA1 Cornu Ammonis 1 CA3 Cornu Ammonis 3 ACC Anterior Cingulate Cortex FMR1 fragile X mental retardation 1 FMRP Fragile X Mental Retardation Protein CA4 Cornu Ammonis 4 KO Knock-out mGluR5 Metabotropic Glutamate Receptor 5 GLT-1 Glutamate Transporter 1 GLAST-1 Glutamate Aspartate Transporter 1 TSP-1 Thrombospondin-1 iPSC Induced pluripotent stem cells YRK1A Dual-specificity tyrosine phosphorylation-regulated kinase-1 STAT Signal Transducer and Activator of Transcription NPC Neural Progenitor Cell A1R Adenosine 1 Receptor DPCPX 8-Cyclopentyl-1,3-dipropyl xanthine Figure 1 Schematic representation illustrating the astrocyte-synapse alterations in Fragile X syndrome (FXS). (1) Astrocyte number is preserved. (2) Reduced astrocyte secreted thrombospondin (TSP-1) prevents spine maturation resulting in more abundant filopodia (immature) spines. (3) Increased S100 calcium-binding protein β (S100β) and GFAP expression has been described in astrocytes. However, this altered expression has not been directly linked with their activity or function. (4) Fragile X Mental Retardation Protein (FMRP) absence in FXS astrocytes leads to metabotropic glutamate receptor 5 (mGluR5) downregulation in astrocytes (yet not in neurons) that negatively regulates glutamate transporter 1 (GLT-1) expression. Impaired glutamate transport due to decreased astrocyte glutamate-aspartate transporter 1 (GLAST-1) and GLT-1 expression increases extracellular glutamate levels (5) and astroglial calcium oscillations (6). This excess of glutamate might activate the postsynaptic mGluR5, which is overexpressed in neurons. (7) mGluR5 and FMRP oppositely regulate mRNA translation at the synapse: mGluR5 promotes it and FMRP prevents it. Therefore, increased mGluR5 expression and lack of FMRP in FXS leads to a disbalance in protein expression levels that account for many of the syndromic features of FXS including an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization that leads to an exaggerated mGluR5-mediated long-term depression (LTD) that is reported in Fmr1 knock-out (KO) mice. Figure 2 Schematic representation illustrating the astrocyte-synapse alterations in DS. (1) Astrocyte number and volume is increased in DS. (2) Reduced astrocyte secreted TSP-1 prevents spine maturation resulting in more frequent filopodia (immature) spines. (3) Increased S100β and GFAP expression has been described in astrocytes. S100β upregulation has been linked with increased astrocyte calcium oscillations (4). Increased astrocyte activity leads to adenosine triphosphate (ATP) release to the synaptic cleft (5) that is hydrolyzed to adenosine and activates A1 adenosine receptors (A1R) (6). A1R activation prevents glutamate release from the presynaptic terminal and, consequently (7) depresses synaptic transmission (8). Even though mGluR5 is upregulated in astrocytes (and probably in neurons), no mechanistic studies have been performed to uncover the contribution of mGluR5 to DS pathophysiology. (9) Reduced glutamate concentrations can be contributed by increased expression of the glutamate transporter GLAST-1 that leads to increased astroglial glutamate uptake. ==== Refs References 1. Dierssen M. Top ten discoveries of the year: Neurodevelopmental disorders Free Neuropathol. 2020 1 13 Available online: https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/2672 (accessed on 26 October 2020) 2. Papazoglou A. Jacobson L.A. McCabe M. Kaufmann W. Zabel T.A. To ID or Not to ID? Changes in Classification Rates of Intellectual Disability Using DSM-5 Intellect. Dev. Disabil. 2014 52 165 174 10.1352/1934-9556-52.3.165 24937742 3. Ardiles A.O. Grabrucker A.M. Scholl F.G. Rudenko G. Borsello T. Molecular and Cellular Mechanisms of Synaptopathies Neural Plast. 2017 2017 1 3 10.1155/2017/2643943 28540088 4. Luo J. Norris R. Gordon S. Nithianantharajah J. Neurodevelopmental synaptopathies: Insights from behaviour in rodent models of synapse gene mutations Prog. Neuro Psychopharmacol. Biol. Psychiatry 2018 84 424 439 10.1016/j.pnpbp.2017.12.001 5. Dierssen M. Ramakers G.J.A. Dendritic pathology in mental retardation: From molecular genetics to neurobiology Genes Brain Behav. 2006 5 48 60 10.1111/j.1601-183X.2006.00224.x 16681800 6. Irwin S.A. Galvez R. Greenough W.T. Dendritic Spine Structural Anomalies in Fragile-X Mental Retardation Syndrome Cereb. Cortex 2000 10 1038 1044 10.1093/cercor/10.10.1038 11007554 7. Dierssen M. Benavides-Piccione R. Martínez-Cué C. Estivill X. Flórez J. Elston G. DeFelipe J. Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: Effects of environmental enrichment Cereb. Cortex 2003 13 758 764 10.1093/cercor/13.7.758 12816891 8. Belichenko P.V. Masliah E. Kleschevnikov A.M. Villar A.J. Epstein C.J. Salehi A. Mobley W.C. Synaptic structural abnormalities in the Ts65Dn mouse model of down syndrome J. Comp. Neurol. 2004 480 281 298 10.1002/cne.20337 15515178 9. Catuara-Solarz S. Espinosa-Carrasco J. Erb I. Langohr K. Gonzalez J.R. Notredame C. Dierssen M. Combined Treatment with Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome eNeuro 2016 3 10.1523/ENEURO.0103-16.2016 10. Comery T.A. Harris J.B. Willems P.J. Oostra B.A. Irwin S.A. Weiler I.J. Greenough W.T. Abnormal dendritic spines in fragile X knockout mice: Maturation and pruning deficits Proc. Natl. Acad. Sci. USA 1997 94 5401 5404 10.1073/pnas.94.10.5401 9144249 11. Hinton V.J. Brown W.T. Wisniewski K. Rudelli R.D. Analysis of neocortex in three males with the fragile X syndrome Am. J. Med. Genet. 1991 41 289 294 10.1002/ajmg.1320410306 1724112 12. Xu X. Miller E.C. Pozzo-Miller L. Dendritic spine dysgenesis in Rett syndrome Front. Neuroanat. 2014 8 10.3389/fnana.2014.00097 25309341 13. Landi S. Putignano E. Boggio E.M. Giustetto M. Pizzorusso T. Ratto G.M. The short-time structural plasticity of dendritic spines is altered in a model of Rett syndrome Sci. Rep. 2011 1 45 10.1038/srep00045 22355564 14. Garcia O. Torres M. Helguera P. Coskun P. Busciglio J. A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down’s Syndrome PLoS ONE 2010 5 e14200 10.1371/journal.pone.0014200 21152035 15. Stagni F. Salvalai M.E. Giacomini A. Emili M. Uguagliati B. Xia E. Grilli M. Bartesaghi R. Bartesaghi R. Neonatal treatment with cyclosporine A restores neurogenesis and spinogenesis in the Ts65Dn model of Down syndrome Neurobiol. Dis. 2019 129 44 55 10.1016/j.nbd.2019.05.005 31085229 16. Jacobs S. Doering L.C. Astrocytes Prevent Abnormal Neuronal Development in the Fragile X Mouse J. Neurosci. 2010 30 4508 4514 10.1523/JNEUROSCI.5027-09.2010 20335488 17. Fukuda T. Itoh M. Ichikawa T. Washiyama K. Goto Y.-I. Delayed Maturation of Neuronal Architecture and Synaptogenesis in Cerebral Cortex ofMecp2-Deficient Mice J. Neuropathol. Exp. Neurol. 2005 64 537 544 10.1093/jnen/64.6.537 15977646 18. Kleschevnikov A.M. Belichenko P.V. Villar A.J. Epstein C.J. Malenka R.C. Mobley W.C. Hippocampal Long-Term Potentiation Suppressed by Increased Inhibition in the Ts65Dn Mouse, a Genetic Model of Down Syndrome J. Neurosci. 2004 24 8153 8160 10.1523/JNEUROSCI.1766-04.2004 15371516 19. Zhao M.-G. Toyoda H. Ko S.W. Ding H.-K. Wu L.-J. Zhuo M. Deficits in Trace Fear Memory and Long-Term Potentiation in a Mouse Model for Fragile X Syndrome J. Neurosci. 2005 25 7385 7392 10.1523/JNEUROSCI.1520-05.2005 16093389 20. Martin H.G.S. Lassalle O. Brown J.T. Manzoni O.J. Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of theFmr1Knockout Mouse Model of Fragile X Syndrome Cereb. Cortex 2015 26 2084 2092 10.1093/cercor/bhv031 25750254 21. Weng S.-M. McLeod F. Bailey M.E.S. Cobb S.R. Synaptic plasticity deficits in an experimental model of rett syndrome: Long-term potentiation saturation and its pharmacological reversal Neuroscience 2011 180 314 321 10.1016/j.neuroscience.2011.01.061 21296130 22. Fred Attneave M.B. Hebb D.O. The Organization of Behavior; A Neuropsychological Theory Am. J. Psychol. 1950 63 633 10.2307/1418888 23. Liu X. Ramirez S. Pang P.T. Puryear C.B. Govindarajan A. Deisseroth K. Tonegawa S. Optogenetic stimulation of a hippocampal engram activates fear memory recall Nat. Cell Biol. 2012 484 381 385 10.1038/nature11028 22441246 24. De La Torre R. De Sola S. Pons M. Duchon A. De Lagran M.M. Farré M. Fitó M. Benejam B. Langohr K. Rodriguez J. Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans Mol. Nutr. Food Res. 2014 58 278 288 10.1002/mnfr.201300325 24039182 25. De La Torre R. De Sola S. Hernandez G. Farré M. Pujol J. Rodriguez J. Espadaler J.M. Langohr K. Cuenca-Royo A. Principe A. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down’s syndrome (TESDAD): A double-blind, randomised, placebo-controlled, phase 2 trial Lancet Neurol. 2016 15 801 810 10.1016/S1474-4422(16)30034-5 27302362 26. Jacquemont S. Berry-Kravis E. Hagerman R. Von Raison F. Gasparini F. Apostol G. Ufer M. Portes V.D. Gomez-Mancilla B. The challenges of clinical trials in fragile X syndrome Psychopharmacology 2014 231 1237 1250 10.1007/s00213-013-3289-0 24173622 27. Perea G. Araque A. Astrocytes Potentiate Transmitter Release at Single Hippocampal Synapses Science 2007 317 1083 1086 10.1126/science.1144640 17717185 28. Adamsky A. Kol A. Kreisel T. Doron A. Ozeri-Engelhard N. Melcer T. Refaeli R. Horn H. Regev L. Groysman M. Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement Cell 2018 174 59 71 10.1016/j.cell.2018.05.002 29804835 29. 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 1229 1239 10.1038/s41593-020-0679-6 32747787 30. 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. Astrocytes contribute to gamma oscillations and recognition memory Proc. Natl. Acad. Sci. USA 2014 111 E3343 E3352 10.1073/pnas.1410893111 25071179 31. 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 144 810 823 10.1016/j.cell.2011.02.018 21376239 32. Cheng C. Lau S.K.M. Doering L.C. Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model Mol. Brain 2016 9 1 15 10.1186/s13041-016-0256-9 26739966 33. Hodges J.L. Yu X. Gilmore A. Bennett H. Tjia M. Perna J.F. Chen C.-C. Li X. Lu J. Zuo Y. Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome Biol. Psychiatry 2017 82 139 149 10.1016/j.biopsych.2016.08.036 27865451 34. Torres M.D. Garcia O. Tang C. Busciglio J. Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome Free. Radic. Biol. Med. 2017 114 10 14 10.1016/j.freeradbiomed.2017.09.025 28965914 35. Dossi E. Vasile F. Rouach N. Human astrocytes in the diseased brain Brain Res. Bull. 2018 136 139 156 10.1016/j.brainresbull.2017.02.001 28212850 36. Simpson J. Ince P. Lace G. Forster G. Shaw P. Matthews F. Savva G. Brayne C. Wharton S.B. Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain Neurobiol. Aging 2010 31 578 590 10.1016/j.neurobiolaging.2008.05.015 18586353 37. Kuchibhotla K.V. Lattarulo C.R. Hyman B.T. Bacskai B.J. Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer Mice Science 2009 323 1211 1215 10.1126/science.1169096 19251629 38. Santello M. Toni N. Volterra A. Astrocyte function from information processing to cognition and cognitive impairment Nat. Neurosci. 2019 22 154 166 10.1038/s41593-018-0325-8 30664773 39. Blanco-Suárez E. Caldwell A.L.M. Allen N.J. Role of astrocyte-synapse interactions in CNS disorders J. Physiol. 2017 595 1903 1916 10.1113/JP270988 27381164 40. Bally B.P. Farmer W.T. Jones E.V. Jessa S. Kacerovsky J.B. Mayran A. Peng H. Lefebvre J.L. Drouin J. Hayer A. Human iPSC-derived Down syndrome astrocytes display genome-wide perturbations in gene expression, an altered adhesion profile, and increased cellular dynamics Hum. Mol. Genet. 2020 29 785 802 10.1093/hmg/ddaa003 31943018 41. Mizuno G.O. Wang Y. Shi G. Wang Y. Sun J. Papadopoulos S. Broussard G.J. Unger E.K. Deng W. Weick J. Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model Cell Rep. 2018 24 355 365 10.1016/j.celrep.2018.06.033 29996097 42. Mito T. Becker L.E. Developmental Changes of S-100 Protein and Glial Fibrillary Acidic Protein in the Brain in Down Syndrome Exp. Neurol. 1993 120 170 176 10.1006/exnr.1993.1052 8491278 43. J∅Rgensen O.S. Brooksbank B.W. Balazs R. Neuronal plasticity and astrocytic reaction in Down syndrome and Alzheimer disease J. Neurol. Sci. 1990 98 63 79 10.1016/0022-510X(90)90182-M 1977892 44. Quinlan R.A. Brenner M. Goldman J.E. Messing A. GFAP and its role in Alexander disease Exp. Cell Res. 2007 313 2077 2087 10.1016/j.yexcr.2007.04.004 17498694 45. Laurence J.A. Fatemi S.H. Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects Cerebellum 2005 4 206 210 10.1080/14734220500208846 16147953 46. Wu Z. Guo Z. Gearing M. Chen G. Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model Nat. Commun. 2014 5 1 13 10.1038/ncomms5159 47. Jo S. Yarishkin O. Hwang Y.J. Chun Y.E. Park M. Woo D.H. Bae J.Y. Kim T. Lee J. Chun H. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease Nat. Med. 2014 20 886 896 10.1038/nm.3639 24973918 48. Gerlai R. Wojtowicz J.M. Marks A. Roder J. Overexpression of a calcium-binding protein, S100 beta, in astrocytes alters synaptic plasticity and impairs spatial learning in transgenic mice Learn. Mem. 1995 2 26 39 10.1101/lm.2.1.26 10467564 49. Durkee C.A. Araque A. Diversity and Specificity of Astrocyte–neuron Communication Neuroscience 2019 396 73 78 10.1016/j.neuroscience.2018.11.010 30458223 50. Panatier A. Robitaille R. Astrocytic mGluR5 and the tripartite synapse Neuroscience 2016 323 29 34 10.1016/j.neuroscience.2015.03.063 25847307 51. Haydon P.G. Glia: Listening and talking to the synapse Nat. Rev. Neurosci. 2001 2 185 193 10.1038/35058528 11256079 52. Araque A. Carmignoto G. Haydon P.G. Oliet S.H.R. Robitaille R. Volterra A. Gliotransmitters Travel in Time and Space Neuron 2014 81 728 739 10.1016/j.neuron.2014.02.007 24559669 53. Ben Achour S. Pont-Lezica L. Béchade C. Pascual O. Is astrocyte calcium signaling relevant for synaptic plasticity? Neuron Glia Biol. 2010 6 147 155 10.1017/S1740925X10000207 21122195 54. Mederos S. Perea G. GABAergic-astrocyte signaling: A refinement of inhibitory brain networks Glia 2019 67 1842 1851 10.1002/glia.23644 31145508 55. Cavaccini A. Durkee C. Kofuji P. Tonini R. Araque A. Astrocyte Signaling Gates Long-Term Depression at Corticostriatal Synapses of the Direct Pathway J. Neurosci. 2020 40 5757 5768 10.1523/JNEUROSCI.2369-19.2020 32541069 56. Araque A. Parpura V. Sanzgiri R.P. Haydon P.G. Tripartite synapses: Glia, the unacknowledged partner Trends Neurosci. 1999 22 208 215 10.1016/S0166-2236(98)01349-6 10322493 57. Volterra A. Liaudet N. Savtchouk I. Astrocyte Ca2+ signalling: An unexpected complexity Nat. Rev. Neurosci. 2014 15 327 335 10.1038/nrn3725 24739787 58. Savtchouk I. Volterra A. Gliotransmission: Beyond Black-and-White J. Neurosci. 2018 38 14 25 10.1523/JNEUROSCI.0017-17.2017 29298905 59. Ventura R. Harris K.M. Three-Dimensional Relationships between Hippocampal Synapses and Astrocytes J. Neurosci. 1999 19 6897 6906 10.1523/JNEUROSCI.19-16-06897.1999 10436047 60. Bushong E.A. Martone M.E. Jones Y.Z. Ellisman M.H. Protoplasmic Astrocytes in CA1 Stratum Radiatum Occupy Separate Anatomical Domains J. Neurosci. 2002 22 183 192 10.1523/JNEUROSCI.22-01-00183.2002 11756501 61. Theodosis D.T. Oxytocin-Secreting Neurons: A Physiological Model of Morphological Neuronal and Glial Plasticity in the Adult Hypothalamus Front. Neuroendocr. 2002 23 101 135 10.1006/frne.2001.0226 11906204 62. Nishida H. Okabe S. Direct Astrocytic Contacts Regulate Local Maturation of Dendritic Spines J. Neurosci. 2007 27 331 340 10.1523/JNEUROSCI.4466-06.2007 17215394 63. Hirrlinger J. Hülsmann S. Kirchhoff F. Astroglial processes show spontaneous motility at active synaptic terminals in situ Eur. J. Neurosci. 2004 20 2235 2239 10.1111/j.1460-9568.2004.03689.x 15450103 64. Chung W.-S. Allen N.J. Eroglu C. Astrocytes Control Synapse Formation, Function, and Elimination Cold Spring Harb. Perspect. Biol. 2015 7 a020370 10.1101/cshperspect.a020370 25663667 65. Van Horn M.R. Ruthazer E.S. Glial regulation of synapse maturation and stabilization in the developing nervous system Curr. Opin. Neurobiol. 2019 54 113 119 10.1016/j.conb.2018.10.002 30347385 66. Christopherson K.S. Ullian E.M. Stokes C.C. Mullowney C.E. Hell J.W. Agah A. Lawler J. Mosher D.F. Bornstein P. Barres B.A. Thrombospondins are Astrocyte-Secreted Proteins that Promote CNS Synaptogenesis Cell 2005 120 421 433 10.1016/j.cell.2004.12.020 15707899 67. Nishiyama H. Knöpfel T. Endo S. Itohara S. Glial protein S100B modulates long-term neuronal synaptic plasticity Proc. Natl. Acad. Sci. USA 2002 99 4037 4042 10.1073/pnas.052020999 11891290 68. Morquette P. Verdier D. Kadala A. Féthière J. Philippe A.G. Robitaille R. Kolta A. An astrocyte-dependent mechanism for neuronal rhythmogenesis Nat. Neurosci. 2015 18 844 854 10.1038/nn.4013 25938883 69. Ahlemeyer B. Beier H. Semkova I. Schaper C. Krieglstein J. S-100β protects cultured neurons against glutamate- and staurosporine-induced damage and is involved in the antiapoptotic action of the 5 HT1A-receptor agonist, Bay x 3702 Brain Res. 2000 858 121 128 10.1016/S0006-8993(99)02438-5 10700604 70. Mori T. Tan J. Arendash G.W. Koyama N. Nojima Y. Town T. Overexpression of Human S100B Exacerbates Brain Damage and Periinfarct Gliosis after Permanent Focal Ischemia Stroke 2008 39 2114 2121 10.1161/STROKEAHA.107.503821 18451356 71. Villarreal A. Avilés-Reyes R. Angelo M.F. Reines A.G. Ramos A.J. S100B alters neuronal survival and dendrite extension via RAGE?mediated NF??B signaling J. Neurochem. 2011 117 321 332 10.1111/j.1471-4159.2011.07207.x 21291473 72. Benchenane K. Tiesinga P.H. Battaglia F.P. Oscillations in the prefrontal cortex: A gateway to memory and attention Curr. Opin. Neurobiol. 2011 21 475 485 10.1016/j.conb.2011.01.004 21429736 73. Escuela D.O.B. Carlsson J. Ambrogini P. Narváez M. Wydra K. Tarakanov A.O. Li X. Millón C. Ferraro L. Cuppini R. Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease Front. Cell. Neurosci. 2017 11 10.3389/fncel.2017.00037 74. Durkee C.A. Covelo A. Lines J. Kofuji P. Aguilar J. Araque A. G i/o protein-coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission Glia 2019 67 1076 1093 10.1002/glia.23589 30801845 75. Doron A. Goshen I. Investigating the transition from recent to remote memory using advanced tools Brain Res. Bull. 2018 141 35 43 10.1016/j.brainresbull.2017.09.005 28939475 76. Frankland P.W. Bontempi B. The organization of recent and remote memories Nat. Rev. Neurosci. 2005 6 119 130 10.1038/nrn1607 15685217 77. Moscovitch M. Cabeza R. Winocur G. Nadel L. Episodic Memory and Beyond: The Hippocampus and Neocortex in Transformation Annu. Rev. Psychol. 2016 67 105 134 10.1146/annurev-psych-113011-143733 26726963 78. Araujo B.H.S. Kaid C. De Souza J.S. Da Silva S.G. Goulart E. Caires L.C.J. Musso C.M. Torres L.B. Ferrasa A. Herai R. Down Syndrome iPSC-Derived Astrocytes Impair Neuronal Synaptogenesis and the mTOR Pathway In Vitro Mol. Neurobiol. 2017 55 5962 5975 10.1007/s12035-017-0818-6 29128905 79. Murphy G.M. Ellis W.G. Lee Y.-L. Stultz K.E. Shrivastava R. Tinklenberg J.R. Eng L.F. Chapter 40: Astrocytic Gliosis in the Amygdala in Down’s Syndrome and Alzheimer’s Disease Elsevier Amsterdam, The Netherlands 1992 Volume 94 475 483 80. Guttenplan K.A. Stafford B.K. El-Danaf R.N. Adler D.I. Münch A.E. Weigel M.K. Huberman A.D. Liddelow S.A. Neurotoxic Reactive Astrocytes Drive Neuronal Death after Retinal Injury Cell Rep. 2020 31 107776 10.1016/j.celrep.2020.107776 32579912 81. Kia A. McAvoy K. Krishnamurthy K. Trotti D. Pasinelli P. Astrocytes expressing ALS-linked mutant FUS induce motor neuron death through release of tumor necrosis factor-alpha Glia 2018 66 1016 1033 10.1002/glia.23298 29380416 82. Sofroniew M. Astrogliosis Cold Spring Harb. Perspect. Biol. 2015 7 a020420 10.1101/cshperspect.a020420 25380660 83. Pekny M. Pekna M. Astrocyte Reactivity and Reactive Astrogliosis: Costs and Benefits Physiol. Rev. 2014 94 1077 1098 10.1152/physrev.00041.2013 25287860 84. Sofroniew M. Molecular dissection of reactive astrogliosis and glial scar formation Trends Neurosci. 2009 32 638 647 10.1016/j.tins.2009.08.002 19782411 85. Griffin W. Sheng J.G. McKenzie J.E. Royston M.C. Gentleman S.M. Brumback R.A. Cork L.C. Del Bigio M.R. Roberts G.W. Mrak R.E. Life-long Overexpression of S100β in Down’s Syndrome: Implications for Alzheimer Pathogenesis Neurobiol. Aging 1999 19 401 405 10.1016/S0197-4580(98)00074-8 86. Banerjee A. Ifrim M.F. Valdez A.N. Raj N. Bassell G.J. Aberrant RNA translation in fragile X syndrome: From FMRP mechanisms to emerging therapeutic strategies Brain Res. 2018 1693 24 36 10.1016/j.brainres.2018.04.008 29653083 87. Dockendorff T.C. Labrador M. The Fragile X Protein and Genome Function Mol. Neurobiol. 2018 56 711 721 10.1007/s12035-018-1122-9 29796988 88. Reiss A.L. Aylward E. Freund L.S. Joshi P.K. Bryan R.N. Neuroanatomy of fragile X syndrome: The posterior fossa Ann. Neurol. 1991 29 26 32 10.1002/ana.410290107 1996876 89. Sabaratnam M. Pathological and neuropathological findings in two males with fragile-X syndrome J. Intellect. Disabil. Res. 2000 44 81 85 10.1046/j.1365-2788.2000.00261.x 10711653 90. The Dutch-Belgian Fragile X Consorthrum. Fmr1 knockout mice: A model to study fragile X mental retardation Cell 1994 78 10.1016/0092-8674(94)90569-x 91. Higashimori H. Morel L. Huth J. Lindemann L. Dulla C. Taylor A. Freeman M. Yang Y. Astroglial FMRP-dependent translational down-regulation of mGluR5 underlies glutamate transporter GLT1 dysregulation in the fragile X mouse Hum. Mol. Genet. 2013 22 2041 2054 10.1093/hmg/ddt055 23396537 92. Bear M.F. Huber K.M. Warren S.T. The mGluR theory of fragile X mental retardation Trends Neurosci. 2004 27 370 377 10.1016/j.tins.2004.04.009 15219735 93. Dölen G. Osterweil E. Rao B.S.S. Smith G.B. Auerbach B.D. Chattarji S. Bear M.F. Correction of Fragile X Syndrome in Mice Neuron 2007 56 955 962 10.1016/j.neuron.2007.12.001 18093519 94. Veloz M.F.V. Buijsen R.A. Willemsen R. Cupido A. Bosman L.W. Koekkoek S.K.E. Potters J.W. Oostra B.A. De Zeeuw C.I. The effect of an mGluR5 inhibitor on procedural memory and avoidance discrimination impairments in Fmr1 KO mice Genes Brain Behav. 2012 11 325 331 10.1111/j.1601-183X.2011.00763.x 22257369 95. Pop A.S. Levenga J. De Esch C.E.F. Buijsen R.A. Nieuwenhuizen I.M. Li T. Isaacs A. Gasparini F. Oostra B.A. Willemsen R. (Rob) Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant Psychopharmacology 2012 231 1227 1235 10.1007/s00213-012-2947-y 23254376 96. Aloisi E. Le Corf K. Dupuis J. Zhang P. Ginger M. Labrousse V. Spatuzza M. Haberl M.G. Costa L. Shigemoto R. Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice Nat. Commun. 2017 8 1103 10.1038/s41467-017-01191-2 29062097 97. Carroll R.C. Lissin D.V. Von Zastrow M. Nicoll R.A. Malenka R.C. Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures Nat. Neurosci. 1999 2 454 460 10.1038/8123 10321250 98. Snyder E.M. Philpot B.D. Huber K.M. Dong X. Fallon J.R. Bear M.F. Internalization of ionotropic glutamate receptors in response to mGluR activation Nat. Neurosci. 2001 4 1079 1085 10.1038/nn746 11687813 99. Zakharenko S.S. Zablow L. Siegelbaum S.A. Altered presynaptic vesicle release and cycling during mGluR-dependent LTD Neuron 2002 35 1099 1110 10.1016/S0896-6273(02)00898-X 12354399 100. Huber K.M. Gallagher S.M. Warren S.T. Bear M.F. Altered synaptic plasticity in a mouse model of fragile X mental retardation Proc. Natl. Acad. Sci. USA 2002 99 7746 7750 10.1073/pnas.122205699 12032354 101. Yuskaitis C.J. Beurel E. Jope R.S. Evidence of reactive astrocytes but not peripheral immune system activation in a mouse model of Fragile X syndrome Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2010 1802 1006 1012 10.1016/j.bbadis.2010.06.015 102. Pacey L.K.K. Guan S. Tharmalingam S. Thomsen C. Hampson D.R. Persistent astrocyte activation in the fragile X mouse cerebellum Brain Behav. 2015 5 e00400 10.1002/brb3.400 26516618 103. Cao Z. Hulsizer S. Cui Y. Pretto D.L. Kim K.H. Hagerman P.J. Tassone F. Pessah I.N. Enhanced Asynchronous Ca2+ Oscillations Associated with Impaired Glutamate Transport in Cortical Astrocytes ExpressingFmr1Gene Premutation Expansion J. Biol. Chem. 2013 288 13831 13841 10.1074/jbc.M112.441055 23553633 104. Asch A.S. Leung L.L. Shapiro J. Nachman R.L. Human brain glial cells synthesize thrombospondin Proc. Natl. Acad. Sci. USA 1986 83 2904 2908 10.1073/pnas.83.9.2904 2939460 105. Yu K. Ge J. Summers J.B. Li F. Liu X. Ma P. Kaminski J. Zhuang J. TSP-1 Secreted by Bone Marrow Stromal Cells Contributes to Retinal Ganglion Cell Neurite Outgrowth and Survival PLoS ONE 2008 3 e2470 10.1371/journal.pone.0002470 18575624 106. Adams J.C. Tucker R.P. The thrombospondin type 1 repeat (TSR) superfamily: Diverse proteins with related roles in neuronal development Dev. Dyn. 2000 10.1002/(SICI)1097-0177(200006)218:2<280::AID-DVDY4>3.0.CO;2-0 107. Lu Z. Kipnis J. Thrombospondin 1—A key astrocyte-derived neurogenic factor FASEB J. 2010 24 1925 1934 10.1096/fj.09-150573 20124433 108. Pinter J.D. Eliez S. Schmitt J.E. Capone G.T. Reiss A.L. Neuroanatomy of Down’s Syndrome: A High-Resolution MRI Study Am. J. Psychiatry 2001 158 1659 1665 10.1176/appi.ajp.158.10.1659 11578999 109. Raz N. Torres I.J. Briggs S.D. Spencer W.D. Thornton A.E. Loken W.J. Gunning F.M. McQuain J.D. Driesen N.R. Acker J.D. Selective neuroanatornic abnormalities in Down’s syndrome and their cognitive correlates: Evidence from MRI morphometry Neurology 1995 45 356 366 10.1212/WNL.45.2.356 7854539 110. De Lagran M.M. Benavides-Piccione R. Ballesteros-Yanez I. Calvo M. Morales M. Fillat C. DeFelipe J. Ramakers G.J.A. Dierssen M. Dyrk1A Influences Neuronal Morphogenesis Through Regulation of Cytoskeletal Dynamics in Mammalian Cortical Neurons Cereb. Cortex 2012 22 2867 2877 10.1093/cercor/bhr362 22215728 111. Lott I. Dierssen M. Cognitive deficits and associated neurological complications in individuals with Down’s syndrome Lancet Neurol. 2010 9 623 633 10.1016/S1474-4422(10)70112-5 20494326 112. Griffin W.S. Stanley L.C. Ling C. White L. MacLeod V. Perrot L.J. White C.L. Araoz C. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease Proc. Natl. Acad. Sci. USA 1989 86 7611 7615 10.1073/pnas.86.19.7611 2529544 113. Lockrow J.P. Fortress A.M. Granholm A.-C.E. Age-Related Neurodegeneration and Memory Loss in Down Syndrome Curr. Gerontol. Geriatr. Res. 2012 2012 1 13 10.1155/2012/463909 22545043 114. Goodison K.L. Parhad I.M. White C.L. Sima A.A.F. Clark A.W. Neuronal and Glial Gene Expression in Neocortex of Downʼs Syndrome and Alzheimerʼs Disease J. Neuropathol. Exp. Neurol. 1993 52 192 198 10.1097/00005072-199305000-00002 8492138 115. Kanaumi T. Milenkovic I. Adle-Biassette H. Aronica E. Kovacs G.G. Non-neuronal cell responses differ between normal and Down syndrome developing brains Int. J. Dev. Neurosci. 2013 31 796 803 10.1016/j.ijdevneu.2013.09.011 24113258 116. Guidi S. Bonasoni P. Ceccarelli C. Santini D. Gualtieri F. Ciani E. Bartesaghi R. RESEARCH ARTICLE: Neurogenesis Impairment and Increased Cell Death Reduce Total Neuron Number in the Hippocampal Region of Fetuses with Down Syndrome Brain Pathol. 2007 18 180 197 10.1111/j.1750-3639.2007.00113.x 18093248 117. Hibaoui Y. Grad I. Letourneau A. Sailani M.R. Dahoun S. Santoni F.A. Gimelli S. Guipponi M. Pelte M.F. Bena F.S. Modelling and rescuing neurodevelopmental defect of D own syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21 EMBO Mol. Med. 2013 6 259 277 10.1002/emmm.201302848 24375627 118. Kurabayashi N. Nguyen M.D. Sanada K. DYRK 1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model EMBO Rep. 2015 16 1548 1562 10.15252/embr.201540374 26373433 119. Lorenzi H.A. Reeves R.H. Hippocampal hypocellularity in the Ts65Dn mouse originates early in development Brain Res. 2006 1104 153 159 10.1016/j.brainres.2006.05.022 16828061 120. Contestabile A. Fíla T. Cappellini A. Bartesaghi R. Ciani E. Widespread impairment of cell proliferation in the neonate Ts65Dn mouse, a model for Down syndrome Cell Prolif. 2009 42 171 181 10.1111/j.1365-2184.2009.00587.x 19317805 121. Anderson A.J. Stoltzner S. Lai F. Su J. Nixon R.A. Morphological and biochemical assessment of DNA damage and apoptosis in Down syndrome and Alzheimer disease, and effect of postmortem tissue archival on TUNEL Neurobiol. Aging 2000 21 511 524 10.1016/S0197-4580(00)00126-3 10924764 122. Halassa M.M. Fellin T. Takano H. Dong J.-H. Haydon P.G. Synaptic Islands Defined by the Territory of a Single Astrocyte J. Neurosci. 2007 27 6473 6477 10.1523/JNEUROSCI.1419-07.2007 17567808 123. Colombo J.A. Reisin H.D. Jones M. Bentham C. Development of interlaminar astroglial processes in the cerebral cortex of control and Down’s syndrome human cases Exp. Neurol. 2005 193 207 217 10.1016/j.expneurol.2004.11.024 15817279 124. Zhang J.-M. Wang H.-K. Ye C.-Q. Ge W. Chen Y. Jiang Z.-L. Wu C.-P. Poo M.-M. Duan S. ATP Released by Astrocytes Mediates Glutamatergic Activity-Dependent Heterosynaptic Suppression Neuron 2003 40 971 982 10.1016/S0896-6273(03)00717-7 14659095 125. Pascual O. Casper K.B. Kubera C. Zhang J. Revilla-Sanchez R. Sul J.-Y. Takano H. Moss S.J. McCarthy K. Haydon P.G. Astrocytic Purinergic Signaling Coordinates Synaptic Networks Science 2005 310 113 116 10.1126/science.1116916 16210541 126. Dunwiddie T.V. Masino S.A. The Role and Regulation of Adenosine in the Central Nervous System Annu. Rev. Neurosci. 2001 24 31 55 10.1146/annurev.neuro.24.1.31 11283304 127. Lindquist B.E. Shuttleworth C.W. Adenosine receptor activation is responsible for prolonged depression of synaptic transmission after spreading depolarization in brain slices Neuroscience 2012 223 365 376 10.1016/j.neuroscience.2012.07.053 22864185 128. Risser D. Lubec G. Cairns N. Herrera-Marschitz M. Excitatory amino acids and monoamines in parahippocampal gyrus and frontal cortical pole of adults with down syndrome Life Sci. 1997 60 1231 1237 10.1016/S0024-3205(97)00067-2 9096240 129. Reynolds G.P. Warner C.E. Amino acid neurotransmitter deficits in adult Down’s syndrome brain tissue Neurosci. Lett. 1988 94 224 227 10.1016/0304-3940(88)90299-6 2907377 130. Begni B. Brighina L. Fumagalli L. Andreoni S. Castelli E. Francesconi C. Del Bo R. Bresolin N. Ferrarese C. Altered glutamate uptake in peripheral tissues from Down Syndrome patients Neurosci. Lett. 2003 343 73 76 10.1016/S0304-3940(03)00260-X 12759167 131. Chen C. Jiang P. Xue H. Peterson S.E. Tran H.T. McCann A.E. Parast M.M. Li S. Pleasure D.E. Laurent L.C. Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells Nat. Commun. 2014 5 4430 10.1038/ncomms5430 25034944 132. Belichenko P.V. Kleschevnikov A.M. Masliah E. Wu C. Takimoto-Kimura R. Salehi A. Mobley W.C. Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of down syndrome J. Comp. Neurol. 2009 512 453 466 10.1002/cne.21895 19034952 133. Harashima C. Jacobowitz D.M. Stoffel M. Chakrabarti L. Haydar T.F. Siarey R.J. Galdzicki Z. Elevated Expression of the G-Protein-Activated Inwardly Rectifying Potassium Channel 2 (GIRK2) in Cerebellar Unipolar Brush Cells of a Down Syndrome Mouse Model Cell. Mol. Neurobiol. 2006 26 717 732 10.1007/s10571-006-9066-4 16783527 134. Best T.K. Cramer N.P. Chakrabarti L. Haydar T.F. Galdzicki Z. Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome Exp. Neurol. 2011 233 749 757 10.1016/j.expneurol.2011.11.033 22178330 135. Costa A.C. Grybko M.J. Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: A model of Down syndrome Neurosci. Lett. 2005 382 317 322 10.1016/j.neulet.2005.03.031 15925111 136. Kurt M. Davies D.C. Kidd M. Dierssen M. Flórez J. Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice Brain Res. 2000 858 191 197 10.1016/S0006-8993(00)01984-3 10700614 137. Oka A. Takashima S. The up-regulation of metabotropic glutamate receptor 5 (mGluR5) in Down’s syndrome brains Acta Neuropathol. 1999 97 275 278 10.1007/s004010050985 10090675 138. Gibson J.R. Bartley A.F. Hays S.A. Huber K.M. Imbalance of Neocortical Excitation and Inhibition and Altered UP States Reflect Network Hyperexcitability in the Mouse Model of Fragile X Syndrome J. Neurophysiol. 2008 100 2615 2626 10.1152/jn.90752.2008 18784272 139. Olmos-Serrano J.L. Paluszkiewicz S.M. Martin B.S. Kaufmann W.E. Corbin J.G. Huntsman M.M. Defective GABAergic Neurotransmission and Pharmacological Rescue of Neuronal Hyperexcitability in the Amygdala in a Mouse Model of Fragile X Syndrome J. Neurosci. 2010 30 9929 9938 10.1523/JNEUROSCI.1714-10.2010 20660275 140. Ethridge L.E. White S.P. Mosconi M.W. Wang J. Byerly M.J. Sweeney J.A. Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome Transl. Psychiatry 2016 6 e787 10.1038/tp.2016.48 27093069 141. Iyer A.M. Van Scheppingen J. Milenkovic I. Anink J.J. Lim D. Genazzani A.A. Adle-Biassette H. Kovacs G.G. Aronica E. Metabotropic Glutamate Receptor 5 in Down’s Syndrome Hippocampus During Development: Increased Expression in Astrocytes Curr. Alzheimer Res. 2014 11 694 705 10.2174/1567205011666140812115423 25115540 142. Piers T.M. Kim D.H. Kim B.C. Regan P. Whitcomb D.J. Cho K. Translational Concepts of mGluR5 in Synaptic Diseases of the Brain Front. Pharm. 2012 3 199 10.3389/fphar.2012.00199 23205012 143. Shiraishi-Yamaguchi Y. Furuichi T. The Homer family proteins Genome Biol. 2007 8 206 10.1186/gb-2007-8-2-206 17316461 144. Won H. Lee H.-R. Gee H.Y. Mah W. Kim J.-I. Lee J. Ha S. Chung C. Jung E.S. Cho Y.S. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function Nat. Cell Biol. 2012 486 261 265 10.1038/nature11208 22699620 145. Gregory K.J. Dong E.N. Meiler J. Conn P.J. Allosteric modulation of metabotropic glutamate receptors: Structural insights and therapeutic potential Neuropharmacology 2011 60 66 81 10.1016/j.neuropharm.2010.07.007 20637216 146. Huber K.M. Role for Rapid Dendritic Protein Synthesis in Hippocampal mGluR-Dependent Long-Term Depression Science 2000 288 1254 1256 10.1126/science.288.5469.1254 10818003 147. Lepannetier S. Gualdani R. Tempesta S. Schakman O. Seghers F. Kreis A. Yerna X. Slimi A. De Clippele M. Tajeddine N. Activation of TRPC1 Channel by Metabotropic Glutamate Receptor mGluR5 Modulates Synaptic Plasticity and Spatial Working Memory Front. Cell. Neurosci. 2018 12 318 10.3389/fncel.2018.00318 30271326 148. Sun Y. Lipton J.O. Boyle L.M. Madsen J.R. Goldenberg M.C. Pascual-Leone A. Sahin M. Rotenberg A. Direct current stimulation induces mGluR5-dependent neocortical plasticity Ann. Neurol. 2016 80 233 246 10.1002/ana.24708 27315032 149. Mor-Shaked H. Eiges R. Reevaluation of FMR1 Hypermethylation Timing in Fragile X Syndrome Front. Mol. Neurosci. 2018 11 31 10.3389/fnmol.2018.00031 29467618 150. Liu X.S. Wu H. Krzisch M. Wu X. Graef J. Muffat J. Hnisz D. Li C.H. Yuan B. Xu C. Rescue of Fragile X Syndrome Neurons by DNA Methylation Editing of the FMR1 Gene Cell 2018 172 979 992.e6 10.1016/j.cell.2018.01.012 29456084 151. Lu J. McCarter M. Lian G. Esposito G. Capoccia E. Delli-Bovi L.C. Hecht J. Sheen V. Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression Hum. Mol. Genet. 2016 25 1714 1727 10.1093/hmg/ddw043 26911678 152. Jin S. Lee Y.K. Lim Y.C. Zheng Z. Lin X.M. Ng D.P.Y. Holbrook J.D. Law H.Y. Kwek K.Y.C. Yeo G.S.H. Global DNA Hypermethylation in Down Syndrome Placenta PLoS Genet. 2013 9 e1003515 10.1371/journal.pgen.1003515 23754950 153. Laufer B.I. Hwang H. Ciernia A.V. Mordaunt C.E. LaSalle J.M. Whole genome bisulfite sequencing of Down syndrome brain reveals regional DNA hypermethylation and novel disorder insights Epigenetics 2019 14 672 684 10.1080/15592294.2019.1609867 31010359 154. De Toma I. Ortega M. Catuara-Solarz S. Sierra C. Sabidó E. Dierssen M. Re-establishment of the epigenetic state and rescue of kinome deregulation in Ts65Dn mice upon treatment with green tea extract and environmental enrichment Sci. Rep. 2020 10 1 18 10.1038/s41598-020-72625-z 31913322