
==== Front
Brain Behav Immun Health
Brain Behav Immun Health
Brain, Behavior, & Immunity - Health
2666-3546
Elsevier

S2666-3546(24)00117-0
10.1016/j.bbih.2024.100839
100839
Full Length Article
Does the kynurenine pathway play a pathogenic role in autism spectrum disorder?
Santana-Coelho Danielle coelhod@uthscsa.edu

Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, TX, USA
06 8 2024
10 2024
06 8 2024
40 10083929 11 2023
28 5 2024
1 8 2024
© 2024 The Author
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication, sociability, and repetitive/stereotyped behavior. The etiology of autism is diverse, with genetic susceptibility playing an important role alongside environmental insults and conditions. Human and preclinical studies have shown that ASD is commonly accompanied by inflammation, and inhibition of the inflammatory response can ameliorate, or prevent the phenotype in preclinical studies. The kynurenine pathway, responsible for tryptophan metabolism, is upregulated by inflammation. Hence, this metabolic route has drawn the attention of investigators across different disciplines such as cancer, immunology, and neuroscience. Over the past decade, studies have identified evidence that the kynurenine pathway is also altered in autism spectrum disorders. In this mini review, we will explore the current status quo of the link between the kynurenine pathway and ASD, shedding light on the compelling but still preliminary evidence of this relationship.

Keywords

Autism spectrum disorder
Inflammation
Maternal immune activation
Kynurenine pathway
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pmc1 Autism spectrum disorder

Autism spectrum disorder is a neurodevelopmental disorder that affects 1 in every 36 children in the United States (CDC, 2020). ASD can manifest as diverse phenotypes of varying severities and the core features are deficits in sociability and communication, and the presence of repetitive/stereotyped behavior. Anxiety, hyperactivity, insomnia, and attention deficit are common comorbidities that present significant overlap in children with ASD and are often underdiagnosed or misdiagnosed (Shaltout et al., 2020).

Understanding the causes of ASD are often challenging. ASD can be classified as syndromic or non-syndromic (idiopathic). Syndromic autism is associated with a neurological syndrome and is often linked to mutations in specific genes. Some of the disorders that can be classified as syndromic ASD, when the individuals present autistic symptoms, are Rett syndrome and Fragile-x syndrome (CDC, 2022). Fragile-X syndrome is considered to be the main known monogenic cause of autism, with 0.5% of people with ASD also having Fragile-X syndrome. The discovery of genes linked to syndromic ASD led to the development of several genetic animal models that are used to aid in the understanding of the role of those genes in the development of autism. Some of the genes known to have a mechanistic role in ASD are the fragile X messenger ribonucleoprotein 1 (FMR1), SH3 and multiple ankyrin repeat domains 3 (Shank 3), tuberous sclerosis complex (TSC), and contactin-associated protein-like 2 (CNTNAP2) (Jang et al., 2023; Jiang et al., 2022; Lin et al., 2016).

Idiopathic (non-syndromic) ASD poses a greater challenge in defining its etiology. Idiopathic autism cannot be explained by a specific mutation or environmental insult. About 85% of ASD cases are of idiopathic origin, and extensive research has been done to identify what factors could be responsible for idiopathic cases (Casanova et al., 2020). Alongside genetic susceptibility, environmental factors also contribute to the development of ASD. Perinatal exposure to drugs, toxins, and infection/inflammation are associated with the development of ASD (Christensen et al., 2013; Flanagan et al., 2023; Karimi et al., 2017). Moreover, a common denominator between these environmental factors is the activation of the immune system (Bilbo et al., 2018).

2 Inflammation during early life may trigger the development of ASD

Inflammation during early life is linked to the etiology of neurodevelopmental disorders. Studies have identified an increased risk of autism in children of mothers who had a severe infection that led to hospitalization during pregnancy (Atladóttir et al., 2010). More recently, Zika and COVID-19 infections during pregnancy have also been associated with an increased risk of neurodevelopmental disorders such as ASD. However, the evidence remains limited due to the recent emergence of these viruses (Edlow et al., 2023; Santi et al., 2021; Shook et al., 2022).

Based on the clinical association between severe inflammation and neurodevelopmental disorders, preclinical studies replicated this phenomenon demonstrating that the activation of the maternal immune system during pregnancy can lead to the development of autistic-like features such as deficits in sociability, decreased sensory gating, impaired social communication, as well as increased repetitive and stereotyped behavior (Tartaglione et al., 2022; Bauman et al., 2014; Scola and Duong, 2017). The maternal immune activation (MIA) model is a well-studied framework for investigating neurodevelopmental disruption caused by early-life inflammation. MIA occurs when the maternal immune system is triggered by an exogenous stimulus such as a virus, a bacteria, or direct administration of pro-inflammatory stimuli such as cytokines. Toll-like receptors (TLRs) are activated in response to immune stimuli facilitating the production of several cytokines and chemokines. This cascade of events leads to alterations in fetal brain development and may result in behavioral deficits later in life (Boulanger-Bertolus et al., 2018; Chen et al., 2019; Minakova and Warner, 2018; Santana-Coelho et al., 2021). The main models of MIA reported in the literature use lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly IC) to induce inflammation. LPS binds to TLR-4 and activates an immune response that mimics a bacterial infection, while Poly IC is a synthetic double-stranded RNA that binds to TLR-3 and mimics a viral infection. These models revealed that the dose and gestational time of the immune challenge dictate distinct phenotypes during adulthood (Boulanger-Bertolus et al., 2018; Hao et al., 2010; Malkova et al., 2012). Additionally, some of those MIA models reproduce the cellular and molecular alterations found in individuals with autism such as dysregulation of the expression of glutamatergic receptors (Khalil et al., 2013), and alterations in dopaminergic and serotonergic neurotransmission (Hsueh et al., 2017).

While the MIA model has been extensively studied, the mechanisms by which the activation of the maternal immune system may lead to a neurodevelopmental disruption are still not well understood. Proinflammatory cytokines, such as interleukin-6 (IL-6), appear to be an important mediator of the developmental disruption that occurs in the Poly IC model. Studies show that inhibition of IL-6 signaling in the placenta can prevent the development of an autistic-like phenotype in rodents (Hsiao and Patterson, 2011; Smith et al., 2007; Wu et al., 2017). Another cytokine implicated in the MIA model is IL-17a. Increased IL-17a levels promote abnormal cortical development, deficits in communication and sociability, and increased repetitive/stereotypical behavior in the offspring (Choi et al., 2016). IL-6 production in response to Poly IC administration stimulates the production of IL-17a from T helper 17 (Th17) cells. This interaction between both cytokines may explain why both have been shown to be sufficient and necessary to the development of the autistic-like phenotype in the MIA model (Hou et al., 2014; Xu and Cao, 2010). Notably, clinical studies have identified increased levels of IL-6 and IL-17a in children with autism which suggests a translational relevance of the findings in preclinical studies (AL-Ayadhi & Mostafa, 2012; Sallam et al., 2024; Tsilioni et al., 2015; Wei et al., 2011; Zhao et al., 2021).

The mechanism downstream of cytokines that causes the development of the autistic-like phenotype in the MIA model is not fully understood. However, it is known that cytokines regulate neuronal proliferation, migration, and differentiation during brain development. Cytokines can also “activate” glial cells such as microglia which are responsible for important developmental processes such as synaptic pruning and plasticity. Abnormal synaptic pruning is believed to be a hallmark of ASD and may be related to the development of the ASD phenotype in the MIA model. Studies show that MIA alters microglia development and phagocytosis (Loayza et al., 2023; Mattei et al., 2017) which can affect synaptic density and could be a mechanism by which inflammation alters brain development. Furthermore, inflammation can alter brain development by changing synaptic density (Coiro et al., 2015), reducing synaptic transmission (Ito et al., 2010), altering GABA developmental shift from being excitatory to inhibitory (Corradini et al., 2017; Fernandez et al., 2019), changing glutamatergic neurotransmission (Mirabella et al., 2021), and reducing neurogenesis (Couch et al., 2021). Together, these alterations contribute to changes in the circuitry with aberrant synaptic connectivity that can lead to ASD-like atypical behavior.

In addition to the evidence linking early-life inflammation to ASD, it is important to note that individuals affected by the disorder have also been found to present with an altered immune system postnatally. Innate immune cells such as monocytes, macrophages, and microglia have been found to have their density and function altered in individuals with ASD. Adolescents with ASD exhibited elevated levels of white blood cells, monocytes, and macrophages with M1 proinflammatory profile compared to controls (Ferencova et al., 2023). A study showed, by using positron emission tomography with a radiotracer for microglia, that young male adults with ASD presented with excessive microglial activation in several brain regions when compared to age and IQ-matched neurotypical controls (Suzuki et al., 2013). Additionally, the adaptive immune response has also been shown to be altered in ASD, with both T cells and B cells being dysregulated. T cells present with upregulated IL-17A signaling and B cells have elevated expression of inflammatory cytokines in ASD individuals (Nadeem et al., 2020, 2022). Another study found that CD14+ T cells from children with ASD challenged with phorbol-12-myristate and ionomycin showed decreased IL-27, and increased IL-21 and IL-22 production compared to control (Ahmad et al., 2017). Furthermore, several cytokines and chemokines have been found to have their levels altered in ASD individuals. Analysis of peripheral blood mononuclear cells identified increased levels of the chemokines CXCR2+, CXCR3+, CXCR5+, and CXCR7+ and CCR3+, CCR5+, CCR7+, and CCR9+ and cytokines IL-1β, IL-4, IFN-γ, and IL-9 in children with ASD (Ahmad et al., 2017, 2018; Ahmad et al., 2017a, Ahmad et al., 2017b). Together, these findings demonstrated that inflammation is an important hallmark of ASD not just during the perinatal period, but also later in development.

3 The kynurenine pathway

The kynurenine pathway (KP) is a primary metabolic route for tryptophan (TRP), responsible for metabolizing over 95% of this essential amino acid. The KP generates several neuroactive metabolites that exert neuromodulatory effects due to its action in glutamatergic and cholinergic receptors. Additionally, inflammation can significantly upregulate KP metabolism. Therefore, the KP has been implicated in mediating inflammation-induced behavioral deficits, due to its potential in modulating neurotransmission. Some of the behavioral phenotypes induced by inflammation that can be mediated by the kynurenine pathway are depressive like-behavior (Lawson et al., 2013), anxiety-like behavior (Salazar et al., 2012), and deficits in recognition memory (Heisler and O’Connor, 2015).

The first step in the kynurenine pathway is the conversion of tryptophan to kynurenine by the enzymes indoleamine 2,3 dioxygenase (IDO) or tryptophan dioxygenase (TDO). Kynurenine (KYN) can be metabolized by kynurenine aminotransferase (KAT) to produce kynurenic acid (KA). Alternatively, kynurenine 3-hydroxylase (KMO) can convert KYN to 3-hydroxykynurenine (3-HK), a precursor of quinolinic acid (QUIN) (Mithaiwala et al., 2021). KA and QUIN are neuroactive metabolites that act as an antagonist and an agonist of N-Methyl-D-aspartate (NMDA) receptors, respectively (Lehmann et al., 1983; Perkins and Stone, 1982). Additionally, KA can inhibit α7 nicotinic acetylcholine (α7nACh), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, exhibit antioxidative properties, and stimulate M-type K+ channels and Aryl hydrocarbon receptors (Ahr). While QUIN is also a modulator of oxidative stress in a dose-dependent manner (Fig. 1) (Kubicova et al., 2013; Wirthgen et al., 2018).Fig. 1 Kynurenine pathway metabolism. The breakdown of tryptophan to kynurenine is done by the enzymes IDO or TDO. IDO can be upregulated by inflammatory cytokines, while TDO can be upregulated by glucocorticoids. Kynurenine, an intermediate metabolite, can undergo three distinct pathways to yield kynurenic acid (KA), 3-hydroxykynurenine (3-HK), and anthranilic acid (AA). KA is produced through irreversible transamination of kynurenine by kynurenine aminotransferases (KAT). It acts as a non-competitive antagonist on ionotropic glutamate receptors (NMDA, AMPA, KA) and α7 nicotinic acetylcholine receptors (α7nAChR). Besides its neuromodulatory effects, KA serves as an agonist for the broadly expressed G-protein-coupled receptor 35 (GPR35) and aryl hydrocarbon receptor (AhR), while also functioning as an ROS scavenger. AA and 3-HK serve as substrates to generate 3-hydroxianthrnalic acid (3-HAA) which is metabolized by 3-hydroxyanthranilate-3,4-dioxygenase (3-HAAO) into 2-amino-3 carboxymuconate semialdehyde. The activity of the enzymes aminocarboxymuconate semialdehyde decarboxylase (ACMSD) will produce picolinic acid (PIC), while quinolinic acid (QUIN) is produced by a spontaneous reaction. QUIN is metabolized by quinolinate phosphoribosyltransferase (QPRT) producing the redox cofactor oxidized nicotinamide adenine dinucleotide (NAD+). In addition to KA, 3-HK, 3-HAA, and QUIN can cause the production of reactive oxygen species (ROS). Created with biorender.com

Fig. 1

Since the KP is regulated by inflammation, this pathway is a potential therapeutic target for a variety of disorders with inflammatory origin. IDO is upregulated by IFN-γ, TNF-α, IL-1β, and IL-6. Some of the same cytokines can also upregulate KMO and kynureninase. Whereas enzymes such as KAT II can be downregulated by IL-1β (reviewed by Campbell et al., 2014). Regarding metabolites, cytokines may elicit differential responses depending on the cell types. For example, developing neurons and astrocytes respond differently to the administration of IL-6. While IL-6 decreases kynurenine levels in astrocytes, it increases kynurenine levels in neurons (Brown et al., 2014). KP-mediated metabolism can also be modulated by inflammatory stimuli induced by bacteria or viruses. LPS administration in rodents upregulates IDO (Williams et al., 2017a), and Poly IC also upregulates IDO in placental trophoblasts, primary human astrocyte cultures, and rodent brains (Suh et al., 2007; Wang et al., 2011; Gibney et al., 2013).

4 Kynurenine pathway's role in development

The KP plays several roles during development. IDO is involved in maternal-fetal tolerance and the enzyme is considered to have an anti-inflammatory function during gestation, as tryptophan metabolism can prevent T-cell dependent inflammatory response toward fetal tissues (Kanellopoulos-Langevin et al., 2003). The placenta expresses all KP enzymes and KP metabolites are present (Manuelpillai et al., 2005; Shayda et al., 2009). Additionally, maternal-derived tryptophan and kynurenine delivery to the fetal compartment is executed by amino acid transporters LAT1 present in the placenta (Chrostowski et al., 2009). Interestingly, the level of kynurenine and its metabolites differs between maternal and fetal tissues, and changes throughout gestation, suggesting that kynurenine metabolism may play different roles during fetal development (Pedraz-Petrozzi et al., 2023; van Zundert et al., 2022).

The role of the KP during the perinatal period has been investigated by studies showing that modulation of the KP has effects on fetal metabolism and development. Goeden and collaborators showed that KYN administration to pregnant dams increased levels of KYN, KA, and 3HK in the placenta, fetal plasma, and fetal brain. While the administration of KA in the dams only increases KA in the placenta (Goeden et al., 2017). This study demonstrated that KYN crossed the placenta while KA did not. Hence, increasing maternal KYN during gestation exposes the fetus to increased levels of KYN that can be further metabolized in the fetal compartment to KA and 3HK. The higher levels of KYN can expose the fetus to downstream metabolites since the expression of KATI, KATII, and KMO in the fetal brain enables KA and QUIN synthesis from KYN (Notarangelo et al., 2019). Interestingly, KYN, KA, and 3-HK in the fetal brain are at higher levels during gestation before steadily decreasing postpartum (Ceresoli-Borroni and Schwarcz, 2000). What function these high levels of metabolites serve in the fetal brain, specifically during gestation, is still unknown. However, it could be related to a disinhibition of glutamatergic receptors during that developmental period.

Due to their opposing actions, KA and QUIN have been implicated in the effects of modulating kynurenine levels during development. Simply put, KA is considered neuroprotective, whereas QA is regarded as a neurotoxic metabolite (Fig. 1). However, high levels of either metabolite during gestation, or disrupted balance between them, likely have adverse effects on brain development and could lead to deficits in behavior. Administration of KYN from gestational days (GD) 15–22 resulted in persistently increased levels of KA at postnatal day (PD) 70; and decreased expression of NMDA receptor subunits, NR1 and NR2A in the fetal brain. These alterations in the KP resulted in deficits in the fear conditioning test in adulthood (Pershing et al., 2016). Likewise, administration of a KMO inhibitor (Ro61-8048) during gestation increased KA levels while decreasing NR2A expression and increasing NR2B expression in the fetal brain. However, the effect of the inhibition of KMO was age-dependent. At PD 21, increased prenatal levels of KA upregulated the expression of NR2A and NR2B accompanied by increased neuronal excitability as measured by recording hippocampal field excitatory postsynaptic potentials (fEPSPs) (Forrest et al., 2013). Exposure to elevated KYN levels during GD 15 to 22 increased the levels of KA in the hippocampus and frontal cortex in males at PD66. While females had increased KA at PD21. High levels of KYN prenatally also induced hippocampal-dependent learning deficits in the Barnes maze test (Buck et al., 2020). Together, these studies suggest that the KP plays an important role in neurodevelopment as altered metabolite levels can disrupt brain development and behavior.

5 The kynurenine pathway and its potential role in autism

5.1 Clinical evidence

One of the first reports indicating that the KP might be involved in the pathophysiology of ASD was published by Boccuto and collaborators in 2013. The study identified a reduced generation of NADH in response to tryptophan in lymphoblastoid cell cultures of individuals with autism. Furthermore, they observed decreased expression of the KP enzymes HAAO and KATII in the cells of ASD individuals when compared to non-ASD controls. Interestingly, the downregulation of the KP metabolism was independent of the underlying cause of ASD and did not appear in the cell lines of patients with intellectual disability who were not diagnosed with ASD, suggesting that these alterations in the KP were specific to ASD (Boccuto et al., 2013).

Subsequent studies have shown that children diagnosed with ASD present with altered tryptophan and kynurenine metabolism. A cross-sectional study with Omani families compared newly diagnosed children with ASD with their age-matched neurotypical siblings and found increased levels of KYN, QUIN, and decreased picolinic acid in serum. As well as increased levels of the cytokines and chemokines IL-1ra, IL-10, IL-17, IP-10, G-CSF, and neopterin, suggesting an immune activation relative to controls (Lim et al., 2016). Another study identified lower levels of KA, KYN, 5-HT in the urine of the ASD group, while xanthurenic acid and QUIN levels were increased (Gevi et al., 2016). Likewise, a study in Norway showed that ASD group had lower levels of KA in the serum when compared to neurotypical children (Bryn et al., 2017). A study comparing different developmental disorders showed that individuals affected by childhood autism and intellectual disability presented with lower levels of KA in the serum, while individuals with Asperger's syndrome presented with lower 5-HT and higher tryptophan levels ( Ormstad et al., 2018). Bilgiç and collaborators showed that children presented higher concentrations of 3-HK and KA in serum when diagnosed with ASD compared to controls. This study excluded children with any allergy or active infection, which diminished the possibility that the alterations identified in the KP were induced by an inflammatory stimulus. Metabolomic profiling of urine from children with idiopathic ASD revealed elevated levels of anthranilic acid, D-neopterin, and 7,8-dihydroneopterin compared to controls (Liang et al., 2020). Collectively, these studies show that kynurenine metabolism is commonly found to be altered in children diagnosed with ASD.

The scientific literature regarding alterations of the KP in adults with autism is scarce. Most studies conducted in adults have investigated the role of tryptophan and serotonin. McDougle and collaborators showed that short-term tryptophan depletion led to the worsening of repetitive and stereotyped behaviors in autistic adults (McDougle et al., 1996). Furthermore, Daly and collaborators showed that short-term tryptophan depletion “normalized” the fronto-cerebellar dysfunctions found in ASD adults during the Go/No-Go task (Daly et al., 2014). Deficits in inhibitory control tested in the Go/No-Go task are suggested to underpin repetitive and stereotyped behaviors which are core features of ASD. Although these studies showed different outcomes for tryptophan depletion, these data indirectly indicate that tryptophan metabolites such as serotonin and kynurenine may play a role in the repetitive/stereotype behavior phenotype typically found in ASD. A study directly assessed the KP in adults with autism and found lower levels of tryptophan and KA in those diagnosed with autism compared to controls and relatives with the broad autism phenotype (BAP) (Carpita et al., 2023).

Overall, these human studies indicate that children and adults diagnosed with ASD present with alterations in tryptophan metabolism and imbalance in the metabolic branches of the KP mainly characterized by lower levels of KA and higher levels of QUIN. While KYN levels both increased and decreased depending on the study. An important caveat is that most of the human studies described here had a higher rate of male participants. Although no sex differences were identified, or not even investigated in some of those studies, it is important to emphasize that males and females with ASD can present differences in phenotype and it is necessary to investigate what causes those differences. The lack of sex differences in those studies may be due to a small sample size of female participants, and not reflect the real differences or commonalities between males and females diagnosed with ASD (Fig. 2).Fig. 2 ASD related alterations in the levels of kynurenine pathway metabolites based on clinical and preclinical studies. Blue arrow up represents increased level of metabolite in ASD samples from human studies. Blue arrow down represents decreased levels of metabolites in ASD samples from human studies. Red arrow up represents increased level of metabolite in ASD animal models. Red arrow down represents decreased levels of metabolites in ASD animal models (Bilgiç et al., 2022; Carpita et al., 2023; Kong et al., 2022; Lim et al., 2016; MacDowell et al., 2021; McTighe et al., 2013; Murakami et al., 2019, Murakami et al., 2021; Notarangelo & Schwarcz, 2021; Ormstad et al., 2018; Williams et al., 2017; Zavitsanou et al., 2014). Created with biorender.com.

Fig. 2

5.2 Preclinical evidence

Alterations in the KP have also been identified in preclinical studies modeling ASD. The first preclinical studies that assessed KP metabolism in models of ASD were published around the same time the first human study was published. McTighe and colleagues demonstrated that BTBR mice, an inbred strain of mice that present with an autistic-like phenotype, have increased KA in the medial prefrontal cortex (McTighe et al., 2013). Another study identified alterations in the KP in a genetic model of ASD. Patched domain containing 1 gene (PTCHD1) mutations are a risk factor for ASD. Knockout mice for Ptchd1 present with increased KYN, AA, KA, 3-HK in the serum at 11 weeks of age. Additionally, the frontal cortex of these mice presented with increased AA, 3-HAA, and 3-HK (Murakami et al., 2019).

Several environmental models of ASD have identified alterations in the KP. Valproate treatment in pregnant rats at GD12.5 caused decreased TRP in the gut. The mice also presented decreased TRP, and increased KYN and QUIN in the brain (Kong et al., 2022). Inflammatory models have also been investigated. Khalil and collaborators assessed if the KP was involved in the MIA model of ASD/schizophrenia. In this study, the authors analyzed the level of KP metabolites after one injection of Poly IC (10 mg/kg) at GD18 and no differences were identified in the whole brain of the rats (Khalil et al., 2013). A study by Zavitsanou and collaborators treated rodents with Poly IC (4 mg/kg) at GD19 and measured serum levels of metabolites at PND 31–33. The study identified increased levels of QA and Picolinic acid, and decreased levels of KA and KYN (Zavitsanou et al., 2014). Rats treated with Poly IC at GD15 have increased expression of IDO1 and decreased expression of TDO2 at postnatal day 35 (Clark et al., 2019). However, mice treated with Poly IC at GD9.5 showed lower KYN levels, and higher levels KMO protein in the frontal cortex. Additionally, the ratio between QUIN and KA for cytotoxicity risk was increased in MIA samples (MacDowell et al., 2021). Alterations in the KP are not unique to the Poly IC model of maternal immune activation. Administration of LPS to pregnant dams at GD15 caused increased levels of KYN, KA, and 3-HK in the fetal brain 4 h after LPS administration. No changes in the KP were identified in the placenta (Notarangelo and Schwarcz, 2021). Another study showed that LPS intrauterine administration at GD28 (late gestation) leads to an upregulation of IDO and KMO in the placenta and the fetal brain 24 h after treatment. The levels of KYN, KA and QUIN were increased in the periventricular region of the fetal brain. While TRP and KYN were decreased in the placenta (Williams et al., 2017b).

Direct manipulation of inflammatory cytokines has also been associated with KP metabolism alterations and autistic-like phenotype in rodents. A study by Murakami and collaborators investigated how an inflammatory insult starting at GD 12.5 causes an autistic-like phenotype. C57BLJ mice were treated with IL-17A plasmid to induce expression of the cytokine IL-17A. Another group of mice was treated with KYN from GD12.5 to 19. Increased IL-17A caused social deficits and increased TRP and KYN in the placenta. Fetal plasma had increased KYN and KA levels. Interestingly, the fetal brain presented a different response depending on the area investigated. The subpallium presented with increased KYN and decreased KA at GD18.5. In contrast, the pallium, increased levels of TRP, KYN, and KA were identified. Increasing KYN prenatally causes similar behavioral deficits to the ones induced by increasing IL-17A. In the adult brain, exposure to IL-17A or KYN prenatally also produced similar effects on the KP metabolism. High KYN decreased the levels of Tryp and increased AA levels in 11-week-old mice's prefrontal cortex (Murakami et al., 2021). The gestational day when an inflammatory insult occurs is key for the development of specific outcomes in the offspring (Estes and McAllister, 2016; Guma et al., 2021, 2022). However, despite time-dependent effects or what immune stimulus was administered, together the data discussed here demonstrate that inflammation during gestation can modulate both the KP and functional outcomes.

5.3 Potential mechanism

As discussed, prenatal inflammation can modulate KP metabolism during development causing behavioral deficits later in life (MacDowell et al., 2021; Zavitsanou et al., 2014). However, the mechanism by which altering the levels of the neuroactive metabolites can disrupt neurodevelopment is not well established. Maternal immune activation upregulates KP metabolism, changing the concentration of the metabolite in the fetal brain. These changes vary depending on the timing of the prenatal insult and the brain regions affected (MacDowell et al., 2021; Murakami et al., 2021).

MIA alters GABAergic and glutamatergic neurotransmission (Corradini et al., 2018; Fernandez et al., 2019; Gillespie et al., 2024; Rahman et al., 2017), similar to prenatal exposure to high levels of kynurenine (Khalil et al., 2014; Murakami et al., 2021). Both QUIN and KA can modulate NMDAr function, and alterations in the levels of these metabolites in the fetal brain can have similar consequences to prenatal inhibition of NMDAr. Furthermore, prenatal NMDAr antagonism causes impaired proliferation of neuronal progenitor, fewer glutamatergic neurons in the prefrontal cortex, and reduces parvalbumin immunoreactivity in the medial prefrontal cortex (Abekawa et al., 2007; Toriumi et al., 2012). Moreover, modulation of NMDAr activity prenatally induced anxiety-like behavior, deficits in cognition, and prepulse-inhibition (Hao et al., 2019). Nevertheless, NMDAr are not the only receptors affected by higher levels of KYN metabolites. Kainate, AMPA, and α7nACh receptors can also be inhibited by KA and other metabolites. Importantly, NMDA, kainate, AMPA, and α7nACh receptors hyper and hypofunction have been associated with ASD phenotype in clinical and preclinical studies. This supports the hypothesis that upregulation of KP metabolism may mediate MIA-induced neurotransmission dysfunction related to ASD-like phenotype (Bacchelli et al., 2015; Nisar et al., 2022) (Fig. 3).Fig. 3 MIA as a risk factor for developmental disorders. The diagram illustrates a model for how MIA may lead to developmental disorders by disrupting the KP metabolism. The maternal immune system can be activated by stimuli, such as infection and stress. This activation causes the production and release of proinflammatory cytokines, which can pass through the placenta and fetal blood brain barrier, thereby upregulating the KP metabolism. As a result, increased levels of kynurenine metabolites, such as KYNA and QUIN, can alter glutamatergic, GABAergic, and cholinergic neurotransmission. These changes can affect synaptogenesis, plasticity, and connectivity during development, ultimately leading to developmental disorders such as ASD and schizophrenia. Created with biorender.com.

Fig. 3

6 Conclusion

Altogether, there is a growing body of evidence suggesting a mechanistic role for the KP in neurodevelopmental disorders such as ASD. Particularly for risk factors that increase maternal and fetal inflammation during gestation. Collectively, the clinical and preclinical studies presented in this mini-review indicate that inflammation and alteration in the level of KP metabolites are commonly found in ASD. Additionally, preclinical studies demonstrate that prenatal inflammation upregulates KP metabolism causing hypo and/or hyperfunction of GABAergic, glutamatergic, and cholinergic neurotransmission. These alterations in neurotransmitter systems affects synaptogenesis, plasticity, and connectivity, ultimately leading to atypical behavior later in life. However, most studies described here are observational, descriptive, or correlational. Thus, new studies are necessary to assess the relationship between inflammation, KP, and ASD in a more direct manner. The development of new techniques that can target specific cell types, new drugs, and spatial analysis to assess where specifically (cell type, brain area …) the alterations are identified will allow the research to move forward in a more mechanistic manner and pinpoint the exact relationship between the KP and ASD.

CRediT authorship contribution statement

Danielle Santana-Coelho: Writing – review & editing, Writing – original draft, Data curation, Conceptualization.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the author used Grammarly in order to improve grammar, punctuation, and readability. After using this tool/service, the author reviewed and edited the content as needed and take full responsibility for the content of the publication.

Declaration of competing interest

None

Data availability

No data was used for the research described in the article.

Acknowledgment

I would like to thank Dr. Jason O'Connor and Dr. David Narvaiz for their valuable feedback in the development of this paper.
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