Abstract
Glutamate receptors in the CNS sensitive to the analog AMPA regulate neuronal excitability and synaptic plasticity. AMPA receptors are usually hetero-tetramers and the human GRIA3 gene and GluA3 protein product have been implicated in various CNS abnormalities including epilepsy, multiple sclerosis, schizophrenia, and cognitive disorders. Although not generally found in the immune system, GRIA3 has recently been demonstrated in a highly specialized group of immune system cells–plasmacytoid dendritic cells (pDCs). These are among the first cells to be activated by infecting viruses and they express GRIA3 in the absence of other AMPA receptor subunits, suggesting a possible role for the subunit in those neuroimmune disorders. The potential for molecular interactions between pDCs and neurons or glia is discussed, with the implications for linking viral infections, pDC activation, and chronic diseases. With growing evidence that the tryptophan metabolite kynurenic acid—an AMPA antagonist—is involved with a similar range of disorders, its role in those links is also discussed.
1 Introduction
Many disorders of the major organ systems and Central Nervous System (CNS) are considered to begin with single, brief episodes of disturbance such as a head trauma or an episode of infection, especially if experienced at a vulnerable time such as pregnancy. It has been difficult to understand the chronic nature of these sequelae without recourse to some form of long-term genetic modification. The recent discovery of a key glutamate receptor subunit in virus-activated cells of the immune system raises the possibility of explaining these disorders by close interactions and macromolecule transfer between cells of the immune system and CNS.
2 AMPA receptors for glutamate in the CNS
Glutamate and its ionotropic receptors responding to the structural analogs kainic acid or α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) are responsible for
the fast depolarization produced by glutamate released at neuronal synapses (; de Leon-López et al., 2025; Diering and Huganir, 2018; Henley and Wilkinson, 2016; Huganir and Nicoll, 2013; Sun et al., 2008). The family of N-methyl-D-aspartate (NMDA)-sensitive receptors generate a slower, more prolonged depolarization which, together with the fast AMPA receptor (AMPAR) activity, are involved in many aspects of neuronal plasticity, learning and cognition. Agonist ligands are of value for disorders involving neural hypo-activity such as cognitive dysfunction, while antagonists reduce the hyper-excitability of seizure disorders (Leo et al., 2018; Perversi et al., 2023). Both types of ligand can limit the effects of neurodegeneration, since agonists improve the declining network activity and antagonists prevent damage to neurons and glia (Rektor, 2013; Russo et al., 2012; ; Ning et al., 2024).
2.1 GRIA3 and GluA3 in the CNS
AMPAR are normally hetero-tetrameric complexes of protein subunits GluA1-GluA4 (genes GRIA1-4). Neurons expressing different combinations of these subunits exhibit marked differences in their electrical properties, including their sensitivity to glutamate, time course of onset and duration of depolarization and repolarization, and the time course of desensitization and re-sensitization (Jacob and Weinberg, 2015; van der Spek et al., 2022). The deletion of GluA3 in particular reduces neural excitability (Reinders et al., 2016; Peng et al., 2022), reduces decay times and impairs neuro-transmission (). Receptor composition also affects cellular trafficking and localization of complete receptors, with profound effects on neural activity (de Leon-López et al., 2025; Ge and Wang, 2021; Henley and Wilkinson, 2016; Shepherd and Huganir, 2007; Diering and Huganir, 2018). However, with this range of properties in the CNS, the GRIA3 gene and its GluA3 subunit protein product have been specifically implicated in many disorders such as those listed in Table 1.
Table 1
| GRIA3-GluA3 modification | Biomedical effects | References |
|---|---|---|
| GRIA3 interacts with Xpo7 protein | regulates cyclic AMP sensitivity; linked to schizophrenia | Toyoda et al., 2025 |
| GluA3 expression | chronic presence of β-amyloid reduced expression | Prinkey et al., 2024 |
| GRIA3 variant | neurodevelopmental changes | Rinaldi et al., 2024 |
| GluA3 dependent effects | β-amyloid inhibition of spine formation and synaptic transmission | Zhang et al., 2023; Reinders et al., 2016 |
| GluA3 expression | reduced in patients with Alzheimer's disease | Zhang et al., 2023; Reinders et al., 2016 |
| GRIA3 variant - pGlu787Lys' | encephalopathy and epilepsy | Melnikova et al., 2022 |
| GRIA3 mutations | linked to epilepsy* consistent with | Rinaldi et al., 2022 |
| GluA3 deficiency | reduced glutamatergic function and increased aggression | Peng et al., 2022 |
| GluA3 | interaction with miRNA-212- p5 linked to lipid accumulation | Hu et al., 2022 |
| GRIA3 polymorphism | Implicated in seizures, autism, schizophrenia | Singh et al., 2022 |
| GRIA3 expression | linked with amphetamine dependence | Iamjan et al., 2018 |
| GluA3 expression | changes in monocytes during pregnancy | |
| GRIA3 expression | linked to migraines | Maher et al., 2013 |
| GluA3 loss | increased striatal [DAm] with enhanced social interaction and aggression | |
| GluA3 expression | increased in CSF of Lewy-Body Disease | Enache et al., 2020 |
| GRIA3 mutation | reduced AMPAR desensitization and increased glutamatergic transmission leading to musculoskeletal dysfunction | Sun et al., 2021; Hamanaka, 2022; Piard et al., 2020 |
| GRIA3 mutations | Seizures produced | Malina et al., 2006; ; Okano et al., 2023; Rinaldi et al., 2022, 2024; Necpál et al., 2023 |
| GluA3 antibodies | linked to epilepsy* | Scheggia et al., 2021 |
| GluA3 deletion | affects sleep quality | ; Volk et al., 2018 |
| GluA3 deletion | inhibited cerebellar function | Gutierrez-Castellanos et al., 2017 |
| GluA3 Ab | associated with tau phosphorylation and cognitive performance | Palese et al., 2020; ; ; Italia et al., 2021, 2022, 2024 |
| GRIA3- GluA3 deletion | inhibits synaptic plasticity and learning | Wang et al., 2011; Meng et al., 2003; Reinders et al., 2016; Peng et al., 2022 |
| GRIA3 expression | correlated with cognitive decline in Alzheimer's but not Parkinson's or Lewy Body dementia | |
| GRIA3 interactions | induces flop variants of other subunits, producing faster kinetics, transmission decay and desensitization;—deletion reduces decay time | |
| GluA3 expression and activity | expression increased in models of Alzheimer's disease, but β-amyloid inhibits activity | Renner et al., 2017; Jia and Collingridge, 2017; Milham et al., 2024 |
| GRIA3 loss in cingulate cortex | X-linked mental retardation | Wu et al., 2007; Gecz et al., 1999; |
| GRIA3- silencing mutation | epilepsy and intellectual disability | |
| GluA3 deletion | linked to Autism Spectrum Disorder | Guilmatre et al., 2009 |
| GluA3 deletion | reduced synaptic efficacy in amygdala | Humeau et al., 2007 |
| GluA3 antibodies | Rasmussen's encephalitis (includes frequent seizures, paralysis and cognitive dysfunction) | Rogers et al., 1994 |
Physiological and pathological involvement of the GRIA3-GluA3 axis.
Examples of the relationship between GRIA3-GluA3 and clinical disorders.
*A role for AMPARs in seizures is supported by use of anticonvulsant drugs such as perampanel and talampanel, which are selective antagonists on AMPARs (Yuan et al., 2019).
2.2 Structural features of AMPARs
AMPAR subunits have usually been found naturally in combination with at least one other subunit, even though individual subunits may influence only some aspects of the full receptor activity. In the complex of GluA2 and GluA3, for example, it is GluA3 that has the dominant and significant influence on synaptic speed, promoting synaptic vesicle release and plasticity (). Increased levels of cyclic AMP increase the conductance specifically of GluA3-operated channels leading to a potentiation of transmission (Renner et al., 2017). In developing brain, thalamic neurotransmission is mediated almost exclusively by AMPAR composed only of GluA3 and GluA4 subunits (Wang et al., 2011) but only the deletion of GluA3 affected learning-induced synaptic plasticity (Reinders et al., 2016; Meng et al., 2003).
All four AMPAR subunits (GluA1-4) can assemble into homomeric or heteromeric receptors when expressed in appropriate cells (Traynelis et al., 2010; Szymanska et al., 2017a,b; , ; Nakanishi et al., 1990; Wenthold et al., 1996; Ge and Wang, 2021) and all those combinations respond to glutamate, the natural ligand (; Kristensen et al., 2011).
2.3 GRIA3 and GluA3 in the immune system
Although GluA3 is primarily expressed by neurons and glia in the CNS, a recent study of all the glutamate receptors found that GRIA3 was expressed at a relatively high level in a small population of highly specialized leucocytes in the immune system—the plasmacytoid dendritic cells (pDCs) (). Of the many varieties of leucocytes in the immune system, pDCs exhibit a special relationship with the GRIA3-GluA3 axis. The cells comprise < 0.5% of the total leucocyte population in humans. They can arise from common lymphoid or myeloid progenitors (Facchetti et al., 1988a), with properties typical of classical DCs (cDCs) but expressing a marker profile which includes CD74 (the MHC-Class II invariant chain), CD123, CD303, CD304 (Facchetti et al., 1988b) and interleukin-7-receptor (IL7R) (Rodrigues and Tussiwand, 2020). Unlike cDCs, they are found mainly in the blood and lymphoid organs (Facchetti et al., 1988b), with unique features not found in cDCs (). Three subsets of pDCs have been recognized in pDCs activated by influenza infection, the transcript for GRIA3 being modestly higher in the P3 pDC subset (PD-L1-CD80+) compared to the P1 (PD-L1+CD80-) subset with the P2 subset (PD-L1+CD80+) having intermediate expression ().
Although pDCs do not proliferate directly, activation promotes their maturation to cDC-like cells which do proliferate (Soumelis and Liu, 2006). More pDCs are then produced de novo so that their overall number remains unchanged or increases relative to the normal steady state. Functionally, pDCs are considered to bridge the processes of innate and adaptive immunity (Li et al., 2017), with a significant influence on autoimmune disorders such as Systemic Lupus Erythematosus (SLE) and rheumatoid arthritis (; Swiecki and Colonna, 2010; Jegalian et al., 2009). After activation their differentiation to cDCs leads to an expansion of anti-inflammatory regulatory T cells (Stone and Williams, 2023), but a major part of their functional importance is that they are the first cells to detect viral infections ().
2.4 pDC activation by viruses
Overall, pDCs are crucial regulators of autoimmune and allergic reactions (Takagi et al., 2011; Villadangos and Young, 2008; ; ; Rowland et al., 2014). The presence of viral nucleic acid fragments in pDCs activates intracellular Toll-Like Receptors (TLR), mainly TLR7 and TLR9. Viral exposure induces pDCs to differentiate into cDC-like cells and, under the chemoattractive influence of the chemokine CCR7, to migrate to the blood and lymphoid organs where they modulate T cell development. The maturation of pDCs is accompanied by the expression of MHC Class I and II molecules necessary for interactions with both CD8+ and CD4+ T cells, respectively (Villadangos and Young, 2008; Jegalian et al., 2009). The immediate response to viral stimulation is to generate type I interferons (IFNα- and β-) which then induce IFN-γ in macrophages and Natural Killer (NK) cells. They also express large quantities of pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) (Wacleche et al., 2018; Reizis, 2019) along with modulators of T cell activity which limit inflammation in tissues including the CNS (Mundt et al., 2019; Giles et al., 2018; Stone and Williams, 2023).
2.5 GluA3 “flip” in pDCs
A remarkable feature of the GRIA3 gene in pDCs is that it is expressed alone, in the absence of any other AMPAR subunits (). These subunits will be available in their singlet form but may also be able to form stable homomeric receptors and behave as fully functional AMPARs as discussed below.
In neurons, GluA3 can exist in two molecular conformations known as “flip” and “flop,” with the “flop” molecules exhibiting greater conformational flexibility, reducing channel open time and the rate of desensitization (Pei et al., 2007, 2009). Developmental or activity-dependent changes in the ratio between the variants is a recognized mechanism of feedback control of excitability and plasticity which is still observed when the isoforms are expressed in a range of cell types (Nishimura et al., 2000; ; Wang et al., 2016). Although GluA3 in pDCs is entirely in the ‘flip' conformation () its presence in cells expressing other subunits promotes their insertion as the “flop” forms. This causes synaptic potentials to exhibit faster kinetics with more rapid decay and desensitization times which affect behavioral cognitive performance. These contributions of GluA3 to the regulation of plasticity and cognition is dependent on cyclic AMP, probably because of its direct association with “Exchange Protein directly Activated by cyclic AMP-2” (Epac2) (Zhang et al., 2024; Renner et al., 2017). In addition, there are significant pharmacological differences between the two variants (Sekiguchi et al., 2002; Schmid et al., 2001; Stine et al., 2001). The relative amounts of “flip” and “flop,” in the CNS, for example, are region-dependent, with up to 3-fold more flop than flip in the CA1 hippocampus, but 3-fold more flip than flop in the CA3 region. These levels can be affected by a range of drugs such as opiates (Park et al., 2003).
3 GRIA3 and GluA3 in clinical disorders
A fuller understanding of the GRIA3-GluA3 axis is required in view of the wide range of medical conditions in which the combination has been implicated (Table 1). Polymorphisms have been described, especially in subjects with intellectual disabilities, when gene sequencing revealed several missense variants of GRIA3, at least four of which were located in the GluA3 functional domains (Moretto et al., 2018). A total loss of the whole gene was also observed in some cases. An examination of all four subunits identified 32 mutations in the GRIA3 gene, all of which produced changes in response sensitivity, magnitude and time course of cellular responses (XiangWei et al., 2023).
The concept of immune system involvement in CNS function and disease was strengthened by evidence that CD4+ T cells were required for individuals to respond positively to an otherwise neuro-degenerative situation (Kipnis et al., 2004; Kipnis, 2016; Ron-Harel and Schwartz, 2009). Depletion of those cells depressed cognitive function and associated behaviors, which were normalized by the adoptive transfer of fresh T cells. It is possible that the age-related decline in cognitive ability may also be related to impaired adaptive immunity (Ron-Harel and Schwartz, 2009).
While much of the evidence arose from experimental studies, observations of human subjects have confirmed that maternal infection or inflammation during pregnancy significantly increases the risk of behavioral abnormalities in the offspring, most notably those seen in schizophrenia (,; ; Girchenko et al., 2020). Viral infections seem to be particularly involved in the initiation of chronic disorders (Yates and Mulkey, 2024). Indeed, the problem of Infection-Associated Chronic Illnesses (IACI) is increasingly being recognized (Hernandez et al., 2026). Maternal stress also affects development of the embryos and neonates (; Meyer et al., 2008; Meyer and Feldon, 2010) and several psychiatric and neurological disorders are considered to be in this category of “developmental disorders” (Meyer and Feldon, 2010; Hornig et al., 2018; Pearce, 2003; ). Glutamate-releasing neurons have been associated with many of these (Moretto et al., 2018), with schizophrenia in particular being considered to be primarily a result of reduced glutamatergic activity (MacDonald et al., 2015; Tamminga et al., 2012; Stan et al., 2015) and for which agonists for AMPARs (AMPAkines) have been developed for treatment (Lynch and Gall, 2006; Henry et al., 2026). It is potentially highly relevant, therefore, that mutations in the GRIA3-GluA3 axis have been linked with a variety of CNS neurological and psychiatric conditions (Table 1) including schizophrenia. As a pathway able to modulate glutamate receptor function, the metabolism of tryptophan to kynurenine and related compounds may be involved in some cases, as discussed later.
4 Proposal for GRIA3 as a mediator of neuroimmune communication by intercellular transfer
Given the number of medical conditions in which GluA3 has been implicated, the question arises of whether there is any link between the expression of GluA3 alone or as homomers in pDCs and the etiology of those disorders. In particular, the role of pDCs as the initial sensors of viral infection and the subsequent recruitment of other cell groups in the immune system suggests that there might be a mechanism by which activated pDCs could modify cell properties in systemic tissues and the CNS. Two factors would be required for this—the presence of pDCs in the tissues and CNS, and a means of communication between pDCs and other cells including neurons and glia. We propose that the virally-induced activation of pDCs increases their numbers in the CNS and that GRIA3 or GluA3 will transfer from them into neurons or glia. The expression of GluA3 in these cells, as well as resident neurons, could potentiate neuronal responses to the combined influences of neuroglial and inflammatory ligands. While speculative, the additional transfer of GRIA3 or GluA3 (possibly both) from activated pDCs to CNS neurons and glia would then increase GluA3 expression and could produce long-lasting changes in the subunit balance leading to altered neuronal excitability and plasticity. Such changes in neuroglial activity could then contribute to chronic clinical disorders such as epileptic syndromes, schizophrenia and other symptoms of cognitive dysfunction (Table 1; Figure 1). This concept might include the transfer of mutant nucleic acids generated peripherally but then transferred to neuroglia, disseminating any mal-functioning activity to the CNS. It would also be more important when RNA, or single- or double-stranded DNA has been transferred between cells in extracellular vesicles (Rai et al., 2021a,b; O'Brien et al., 2020; Ekström et al., 2012; Payandeh et al., 2024).
Figure 1
In the following sections, we address each of the features and processes that would be necessary for this proposal, indicating how existing evidence on GRIA3 and other AMPAR subunits provide significant support for the concept.
4.1 pDCs in the CNS
Although there are few DCs present in the normal, uninjured CNS parenchyma, they do enter the brain if there is local damage from an injury or stroke, or during peripheral inflammation, infections or exposure to stress (Serafini et al., 2006; Zozulya et al., 2010; Yogev et al., 2012; Hoye et al., 2018). Following an episode of cerebral ischaemia, activated microglia attract the movement of DCs into the brain parenchyma, including cDCs and pDCs (Gallizioli et al., 2020). The trafficking of pDCs into the CNS is regulated partly by microRNA species (Hoye et al., 2018) and chemokines such as CCL17 (Ruland et al., 2017), with recruitment enhanced in the early stages of the multiple sclerosis model Experimental Allergic Encephalomyelitis (EAE) (Sie et al., 2019). Cytoskeletal changes are also involved (Meena et al., 2021).
The role of pDCs may then become pivotal since the IFN-β produced by them will contribute to the further influx of cDCs (Pennell and Fish, 2017) and their promotion of regulatory T-cells (Tregs) differentiation and immune tolerance. Similarly, the expression of MHC (Major Histocompatibility Complex) proteins and T cell activation modulators such as CD80 and CCR7 persists for long periods after inflammation (; ). Increased pDC penetration to the CNS is seen in the early stages of autoimmune disorders such as MS / EAE, when they contribute to the suppression of local CD4+ T cells and reduce the severity of disease (Duraes et al., 2016; ; Giles et al., 2018; Mundt et al., 2019). Conversely, their depletion increases central CD4+ activation and IFN-γ generation, exacerbating the condition (; ).
An additional consideration of immune system cells in the CNS is that following infections, systemic inflammation or cerebral incidents such as vascular infarcts and the resulting higher rates of cell death, there will be an increased permeability of the blood-brain barrier, allowing increased movements of cells and molecules between immune system cells and the CNS (Figure 1). This could represent one explanation of the development of neuro-psychiatric disorders in the aftermath of physical trauma, infection or chronic stress, for example, which would further increase the cell and molecular movements described above.
4.2 GluA3 receptors in pDCs
The intercellular movement of AMPAR subunits or intact tetrameric receptors has been observed, with efficient transfers of each of the subunits (Peters et al., 2021; Ge and Wang, 2021; Zachariassen et al., 2016; Rinaldi et al., 2024; Hennegriff et al., 1997). All AMPAR subunits can form homomeric receptors with electrophysiological activity in sensitive patch clamp studies (Sudo et al., 1997, 1999), while their combined transfection—for instance GluA1 and GluA2—produces heteromeric combinations of the same stoichiometry as natural GluA1/GluA2 receptors (Nishimura et al., 2000; Ge and Wang, 2021). This organization may be related to the continuous recycling of the composite mixtures between their endosomal location and the postsynaptic membrane. These receptors are trafficked to the cell membrane and exhibit functional activity comparable with the natural receptors (Rinaldi et al., 2024; Toyoda et al., 2007). With neurons, the expression of physiological functionality extends to their electrophysiological properties (Neve et al., 1997) and AMPAR subunits transfected into hippocampal neurons by viral transfer produce functional receptor combinations in intact multi-neuronal circuits (Kakegawa et al., 2004).
Clearly, the presence of GRIA3 alone in pDCs precludes the formation of heteromeric receptors, but the translation of GRIA3 RNA into the GluA3 (flip) protein has been reported many times (Varney et al., 1998; Poon et al., 2010; Pokharna et al., 2025; ; Holley et al., 2012; Yuan et al., 2019; Man et al., 2000a,b; Limon et al., 2007; ; Ge and Wang, 2021; Zachariassen et al., 2016; Hennegriff et al., 1997). Homomeric GluA3 receptors behave as fully functional AMPARs, being activated by glutamate and blocked by the general quinoxaline-based AMPA antagonists such as CNQX and NBQX (Tondreau et al., 2008; Holley et al., 2012; Fukushima et al., 2020) as well as the AMPA-selective anticonvulsant drug perampanel (Yuan et al., 2019). An important feature of GluA3 is that its molecular structural flexibility predisposes it to interact preferentially with other AMPAR subunits (Sukumaran et al., 2011; ; Zhao et al., 2016). As a result, GluA3 homomers can only form in significant numbers in the absence of other subunits (Greger et al., 2017; Hansen et al., 2021; , ). This makes the presence of homomeric GluA3 complexes in pDCs easier to understand, as no other subunits are present. The significance of this will be addressed later.
However, it should be noted that the format of GluA3 expression and the question of functionality are not a central issue in the current proposal. Multi-unit receptors may be involved where functional responses have been obtained, since the individual subunits would probably not be functionally competent, but this not would be required for our proposal: pDCs expressing only singlet subunits would still be able, in principle, to transfer these to other cells using the various mechanisms discussed below. Our proposal is predicated only on the viral activation of pDCs and their transference of GRIA3 or GluA3 to cells where its influence will affect activity.
4.3 Intercellular molecular transfer
The fundamental importance of the intercellular transfer of proteins, RNA and DNA molecules has been recognized for more than 25 years (Valadi et al., 2007; Davis, 2007; ; Lanna et al., 2022; Simons and Raposo, 2009; Diehl et al., 2008). The nuclear machinery and subsequent endosomal sorting produces functional receptor complexes of the same multimeric subunit combinations that occur naturally in similar populations of the recipient cells as noted above for GluA1/GluA2 and GluA3/GluA4 combinations. The process of intercellular transfer is sometimes referred to as “lateral (or horizontal) gene transfer” by analogy with the process originally demonstrated in prokaryotes and essential for environmental adaptation and antimicrobial resistance (Keeling and Palmer, 2008; ; Soucy et al., 2015; Emamalipour et al., 2020). The process is considered physiologically important in many situations such as neuronal network integration and for the development of tumor resistance (Valcz et al., 2022) (Figure 1).
The fidelity of the transfected cell properties compared with natural cells has been confirmed by the selectivity and potency of antagonists (Nielsen et al., 1998).
For pDCs and other immune system cells, the most likely mechanism of interaction is the movement of molecules between cells. In addition to the very rapid, millisecond duration, changes of excitability mediated via synaptic transmission, cells in the CNS—and most other tissues—also exchange molecular information on slower time scales. This can include the movement of molecules from one cell to another via the intercellular fluid. All extracellular (inter-cellular) body fluids contain a variety of macromolecules, including circulating cell free (cf)RNA or cfDNA, and proteins including many enzymes (Stewart and Tsui, 2018; Yao et al., 2016; Thierry et al., 2016; Tamkovich et al., 2006; Jiang and Lo, 2016; Sun et al., 2015; Lehmann-Werman et al., 2016). They are often the result of cell damage or death but, since ongoing cell death is a feature of all living organisms, they are present in normal, as well as ill, populations (Yeri et al., 2017; Zhou et al., 2021, 2022). The principle of intercellular transfers of such macromolecules between immune system cells has become well established (Groc and Choquet, 2006). From the extracellular medium, these molecules can be exchanged between cells via the common processes of exocytosis and endocytosis, both of which have been demonstrated to occur with AMPAR subunits (Hirano, 2018). The differential secretion by exocytosis of proteins and nucleic acids, followed by their endocytosis into other cells, has been specifically proposed as an important factor in the frequently observed mismatch between gene and protein expression in many cells (Jiang et al., 2020).
These molecular movements may involve diffusion or active transport of the molecules themselves, although many macromolecules can be ferried between cells as cargo in cell organelles and extracellular vesicles (Figure 1) (Nevarez-Ramirez et al., 2023; Thierry et al., 2016; Yeri et al., 2017; Yu et al., 2015; Yang et al., 2017; Shao et al., 2015; Huang et al., 2013; Li et al., 2014; Lunavat et al., 2015). The general term Extracellular Vesicles (EVs) includes structures such as microvesicles and exosomes with a range of sizes from 20–500 nm (Raza et al., 2016; ) although the description and definition of these is in need of clarification (Torres and Lee, 2023). The particular importance of EVs arises partly from their ability to transfer a wide range of molecular “cargoes” of proteins and genetic material, including RNA and single- or double-stranded DNA (Rai et al., 2021a,b; O'Brien et al., 2020; Ekström et al., 2012; Payandeh et al., 2024). The movement of molecules by EVs does result in functional changes in the recipient cells' behavior and fundamental properties such as apoptosis and metastasis (Thery et al., 2009). Neurons secrete and absorb EVs with effects on axonal structure and the formation or pruning of synapses in addition to excitability and plasticity (Torres and Lee, 2023; Raza et al., 2016). EVs may also transfer mutated molecules, thus effecting a form of epigenetic, instant evolution on the tissue system concerned (Jahan et al., 2022).
Related to the vesicles are “nanotubes,” filamentous structures commonly found in the CNS physically bridging the space between neurons and glial cells (Figure 1). These are relatively large structures—around 50 μm wide and 50–500 μm long, although even larger ones have been reported. They conduct a wide variety of molecules and can even conduct organelles including mitochondria (; ; Jahan et al., 2022).
Molecular transfer can also include trogocytosis—the absorption of part of a cell that has been described in many cases including T and B lymphocytes, Natural Killer cells and antigen presenting cells (,). Very large molecules such as antigenic proteins, MHC proteins and their receptors can be conveyed in this fashion (Zhao et al., 2022; Reed et al., 2021; Nakayama et al., 2021; Miyake and Karasuyama, 2021).
These various processes can transport a wide variety of molecules, small or large, such as nucleic acids or fragments thereof, in addition to proteins, lipids and other compounds () including glutamate receptors (Newpher and Ehlers, 2008). Both GluA1 and GluA3 subunits can be trafficked in this way, although a difference in the sizes of vesicles carrying them suggested a functional mechanism to specify different cell or membrane localizations of the two molecules (Peters et al., 2021). Experimental confirmation that complete genes for receptors exchange between cells and the extracellular medium is exemplified by the demonstration of the presence of glutamate receptor genes in human blood serum and exosomes (Kamyshna et al., 2022; Sanchez-Melgar et al., 2020).
Importantly, the ability of extracellular nucleic acids to enter cells and to integrate into their genome would account for the long-lasting nature of chronic disorders including neurological conditions (Parkinson's disease, schizophrenia, many disorders involving deficits in cognition and mental development) resulting from alterations in AMPAR composition. Those abnormalities would probably be irreversible in view of the high affinity of GluA3 for all other AMPAR subunits.
Indeed, intercellular transfer of the GRIA3 gene would probably integrate into the recipient cells' genomes, causing effects that might be irreversible and require the development of pharmaco-genetic strategies for cure rather than conventional approaches focused on symptom control. Such genetic integration has been demonstrated for a range of molecules including the transfer of intact telomeres from antigen presenting cells (Lanna et al., 2022).
4.4 Transfer between cell types
Importantly for the present discussion, such molecular movements can occur between most types of leucocytes, often of molecules with immunological relevance such as MHC proteins (Zhao et al., 2022). EVs have been identified as a major mechanism for the transfer of genes between leucocytes and CNS neurons and glia (Ridder et al., 2014; Deng et al., 2022). They also carry macromolecules between cells in peripheral organs and tissues to leucocytes (Nevarez-Ramirez et al., 2023) and to neurons or glia (Nishiyama et al., 2016), exemplified by RNA transfer between glia and macrophages (Paolicelli et al., 2019). Within the CNS, RNA transfer has been considered crucial to interneuronal integration (Meservey et al., 2021; Zappulli et al., 2016) and has been studied for its contribution to transfers between neurons to leucocytes and vice versa in relation to the genesis of Alzheimer's disease (Deng et al., 2022) (Figure 1).
AMPAR subunits have been shown to transfer between all cell types in the CNS by exocytosis and endocytosis (Hirano, 2018). However, as noted above, the unique flexibility of the GluA3 structure leads it to interact preferentially with the other three AMPAR subunits (). For those pDCs which enter the CNS, therefore, there would be a strong tendency for GluA3 subunits to leave the pDCs and transfer into neurons expressing AMPARs which do not include GluA3. This would apply most to singlet GluA3 subunits, but the greater affinity of GluA3 for other AMPAR subunits would result in any homomers present in pDCs being relatively unstable and ready to “donate” (or lose) individual GluA3 subunits to existing heteromeric complexes in CNS cells. The shift in AMPAR composition would cause a significant change in the electrical and metabolic properties of the recipient cells as noted earlier. Effectively, a bias would develop for the transfer of GluA3 from pDCs to neurons and glia which express those other subunits. The pDCs would be acting as a source or reservoir of GluA3, whereas cells with different subunits would attract GluA3 to form functional GluA3-containing heteromers.
Adding to these forces is that the “flip” variants of AMPAR subunits in pDCs can be actively secreted by cells, whereas the “flop” isoform tends to be retained intracellularly, mainly associated with endoplasmic reticulum (). Since the GluA3 isoform in pDCs is entirely in the “flip” variety (), the subunits are more likely to be shed than other subunits and hence more amenable to transfer into cells expressing other AMPAR subunits where they would significantly alter cell properties.
These consideration are especially relevant to the presence of GRIA3-GluA3 expression as mediators of neuroimmune communication in the CNS and immune system cells, since the higher the proportion of GluA3 in the glutamate receptor pool, the more diluted will be the normal multi-unit heteromeric subunits. Since each subunit is linked with specific cell properties, this would change the balance of AMPAR function as a whole. For example, GluA2 is a key factor regulating calcium permeability, while GluA1 has been linked with novelty recognition behavior, learning, and memory (Meng et al., 2003). Their dilution resulting from cells acquiring GluA3 would alter these aspects of physiology indirectly, in addition to the properties introduced by GluA3.
Of course, some molecular transfers may be bidirectional, with some movements occurring from neurons and glia into immune system cells, potentially impacting on immune system function. Such a bi-directional interchange would contribute substantially to the recognized reciprocal influences of neuroimmune communication known as the neuroimmune interface (Zouikr et al., 2017; Stone et al., 2022; Stone and Williams, 2024).
5 A key role for the kynurenine pathway
An additional factor to consider in the context of AMPA receptors is their activation and inactivation, for which it is especially appropriate to consider the kynurenine pathway, the dominant route for tryptophan metabolism (Figure 2). The first enzyme of the pathway is indoleamine-2,3-dioxygenase (IDO1), an enzyme which is powerfully induced by interferon-γ, and whose expression is a key stage in the immune response to challenge, including virus-activated pDCs. Therefore, a viral infection will initiate activity in the kynurenine pathway as a consequence of activating pDCs. The pathway leads to kynurenic acid (Figure 2), an antagonist at all the ionotropic glutamate receptors including AMPAR (activated by quisqualic acid) (Perkins and Stone, 1982; Stone et al., 2013; see Stone, 1993), with additional activity on Aryl Hydrocarbon Receptors (AHR) (Opitz et al., 2011; ) and G-Protein coupled Receptors such as GPR35 (; Resta et al., 2016) and GPR109A proteins (Stone et al., 2022; Stone and Williams, 2024). Kynurenic acid has received much attention as a critical factor in neuroimmune communication because of its regulation of neuronal activity and its promotion of tolerance in the immune system (Stone and Williams, 2023), of which the cross-talk between pDCs and neurons is a specific example. An overview of the kynurenine pathway led to the concept that it operates as an organism-wide “reflex” stress response system. This partly reflects the importance of kynurenic acid acting on AHR to promote differentiation of naïve CD4+ lymphocytes to anti-inflammatory (and anti-autoimmune) Tregs (Huang Y.-S. et al., 2020; Stone and Williams, 2023). This will be amplified by stress-induced glucocorticoids, whether from physical or psychological causes, which activate TDO2, further increasing levels of kynurenic acid in the CNS, where it blocks AMPAR (Figure 2).
Figure 2
Furthermore, the production of TGF-β promotes the expression and activity (enzymatic and non-enzymatic) of IDO1 in IDO1-competent cDCs (; Litzenburger et al., 2014) and pDCs (Pallotta et al., 2011; Li et al., 2016), establishing a positive feedback cycle in the differentiation of Tregs in early phases of adaptive immunity with its additional modulation of neuronal excitability and plasticity (; Stone and Williams, 2023).
An additional product of the kynurenine pathway is quinolinic acid, a selective agonist at the glutamate receptors sensitive to NMDA (Stone, 1993). Activating the kynurenine pathway, therefore, will produce a complex modulation of network activity in the CNS, depending on the relative concentrations of the kynurenine metabolites and the various subtypes of glutamate receptor (Stone and Williams, 2024).
5.1 Kynurenic acid, GluA3, and development
The biological activity of the tryptophan metabolite kynurenic acid was first described using its application to single neurons in anesthetized rats, where it was found to antagonize ligands acting on glutamate receptors. This included blockade of excitation by quisqualic acid, an agonist at the receptors for the later-developed agonist AMPA (Perkins and Stone, 1982; Stone, 1993). Most interest in kynurenic acid has been in its blockade of NMDAR which, as noted above, are a major mediator of neuronal and synaptic plasticity. However, glutamate can only activate NMDARs after initial depolarization by the AMPA and kainate receptors, so these must also be considered as indirect mediators of plasticity, and therefore therapeutic targets comparable with NMDAR.
While the molecular transfer hypothesis could represent one explanation for the development of neuro-psychiatric disorders in the aftermath of physical trauma, infection or chronic stress in individuals of any age (Tioleco et al., 2021; Furman et al., 2019; Solek et al., 2018), it may also be relevant to the disorders initiated by these factors experienced during pregnancy or neonatal life- the so-called “neurodevelopmental disorders.” These are usually considered to be behavioral conditions such as schizophrenia, major depression, and autism spectrum disorders (Jones et al., 2017; ; Krakowiak et al., 2012) and the kynurenine pathway represents a potential link between them.
Infection-induced activation of the kynurenine pathway appears to be a key factor affecting CNS development of the embryo and early neonates. This has given rise to the view that some adult disorders are attributable to factors active early in development (,; Meyer et al., 2008; Meyer and Feldon, 2010). Increased levels of kynurenic acid in the CNS of a gestating rodent dam and its embryo results in widespread changes to the structure, biochemistry, and electrophysiological activity in the brains of offspring, persisting into adulthood (Forrest et al., 2013a,b; Khalil et al., 2014; Pisar et al., 2014; Mithaiwala et al., 2021), with associated changes in several aspects of behavior (; ; Santana-Coelho et al., 2026; Tanaka et al., 2022). This is entirely consistent with extensive evidence from rodents and humans that raised levels of kynurenic acid in the CNS or CSF are related to the early symptoms of schizophrenia (Erhardt et al., 2017; Stone and Darlington, 2013; Kindler et al., 2020; Orhan et al., 2025). Interestingly, the administration of anti-psychotic agents such as clozapine alters GRIA3 expression in the dorsolateral prefrontal cortex, a region pre-eminently linked with the symptoms of schizophrenia (O'Connor and Hemby, 2007; Duric et al., 2013).
A similar etiology may apply to the cognitive deficits in patients with disorders such as autism and dementias (Huang X. B. et al., 2020; Kegel et al., 2017; Santana-Coelho et al., 2026). The reduced cognitive performance can be prevented by inhibiting the formation of kynurenic acid using inhibitors of KAT. Reducing the synthesis of kynurenic acid from tryptophan and kynurenine using inhibitors of KAT2 is a significant objective of pharmaceutical research (Kozak et al., 2014).
A recent meta-analysis has confirmed the view that chronic stress produces a profound shift in the balance between the neuroprotective activity of kynurenic acid, for which the CNS content is reduced, and the excitatory, potentially neurotoxic activity of quinolinic acid, of which the endogenous concentration is raised (de Bartolomeis et al., 2025). The data would be consistent with a role for elevated kynurenic acid in the early stages of disease, noted above, with a shift toward neurodegeneration following chronic stress and contributing to neurodegeneration and resistance to drug therapy caused by excessive levels of quinolinic acid (Magri et al., 2008). There is also a parallel with the negative correlation between quinolinic acid levels in the blood and the loss of cognitive function in patients with schizophrenia (; Stone et al., 2012).
With the strength of this evidence linking kynurenic acid and schizo-affective disorders, and the well-established ability of kynurenic acid to block AMPARs, it is possible that it is the presence of altered AMPAR structures combined with the elevated concentrations of kynurenic acid which becomes sufficient to produce the subtle, albeit disabling, disorders of cognition. While the mutations and other molecular irregularities linked to chronic disorders (Table 1) are likely to be a major cause of chronic dysfunction, this combination could increase the functional impact of both factors. A pharmacological strategy which targets kynurenine metabolism in relation to AMPAR structure could be effective in reducing the incidence of several highly drug-resistant disorders.
5.2 Kynurenines and pDCs
An additional link may exist between the kynurenine pathway and pDCs. It is been claimed that human pDCs have a high expression of IDO1 which is induced when the pDCs are activated by TLR9 (). Certainly the interferons produced by pDCs are able to increase IDO1 activity (). This would be valuable since induction of the kynurenine pathway would generate kynurenine and kynurenic acid which initiate the feedback circuit maintaining immune tolerance (Liu et al., 2014; Lippens et al., 2016) via the AHR and Treg differentiation. Not all pDCs may be involved, however, since it has been suggested that the lymph node population express IDO1, whereas splenic pDCs do not (Puccetti and Fallarino, 2008). In the latter population, reverse signaling via IFN-α and IFN-β may be required for IDO1 expression.
6 Conclusion
The arguments presented lead to the proposal that plasmacytoid dendritic cells, the leucocyte population which initiates the immune response to viral infections, express an atypical AMPA receptor subunit, namely a flip form of GluA3 with properties that could encourage its transfer to cells in the CNS. The GRIA3-GluA3 axis is of fundamental relevance to CNS function, a view supported by the serious medical conditions which result from the loss, mutations or polymorphic variations that have been described for this combination. This would be expected to disrupt normal neuronal circuit activity and lead to the neurological symptoms and disturbed behaviors noted in Table 1. All elements of the proposed links are based on relevant experimental demonstrations and might lead to a consideration of this, or other comparable neuroimmune mechanisms, relevant to understanding the links between infection and disease. The structural stability of AMPARs containing GluA3 in homomeric or heteromeric formations could account for the chronic nature of some illnesses after viral infection. The proposal will require further evidence using specific factors on which the present proposal is based, especially confirmation that GRIA3 or GluA3 can transfer from the pDCs into CNS cells where their increased expression could contribute to the chronic nature of several disorders. Since the kynurenine pathway is also activated by infection and IFN-γ, changes in the production and concentration of the AMPA antagonist kynurenic acid could contribute to those symptoms.
Statements
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References
1
AdamczykA. R.TakamiyaK.YocumJ.KrasnovaI. N.CalderonJ.et al. (2012). GluA3-deficiency in mice is associated with increased social and aggressive behavior and elevated dopamine in striatum. Behav. Brain Res. 229, 265–272. doi: 10.1016/j.bbr.2012.01.007
2
AdamsN. M.DasA.YunT. J.ReizisB. (2024). Ontogeny and function of plasmacytoid dendritic cells. Ann. Rev. Immunol. 42, 347–373. doi: 10.1146/annurev-immunol-090122-041105
3
AgnatiL. F.FuxeK. (2014). Extracellular-vesicle type of volume transmission and tunnelling-nanotube type of wiring transmission add a new dimension to brain neuro-glial networks. Philos. Trans. R Soc Lond B Sci.369:20130505. doi: 10.1098/rstb.2013.0505
4
AgnatiL. F.GuidolinD.GuesciniM.GenedaniS.FuxeK. (2010). Understanding wiring and volume transmission. Brain Res. Rev. 64, 137–159. doi: 10.1016/j.brainresrev.2010.03.003
5
AkinsholaB. E.YasudaR. P.PeoplesR. W.TaylorR. E. (2003). Ethanol sensitivity of recombinant homomeric and heteromeric AMPA receptor subunits expressed in Xenopus oocytes. Alcohol. Clin. Exp. Res. 27, 1876–1883. doi: 10.1097/01.ALC.0000098874.65490.52
6
AlculumbreS. G.Sainy-AndreV.Di DomizioJ.VargasJ. P.SirvenP.BostP.et al. (2018). Diversification of human plasmacytoid predendritic cells in response to a single stimulus. Nat. Immunol. 19, 63–70. doi: 10.1038/s41590-017-0012-z
7
AllenA. S.AggarwalV.BerkovicS. F.CossetteP.DelantyN.DlugosD.et al. (2021). Diverse genetic causes of polymicrogyria with epilepsy. Epilepsia62, 973–983. doi: 10.1111/epi.16854
8
AntunesF. M.RubioM. E.KandlerK. (2020). Role of GluA3 AMPA Receptor subunits in the presynaptic and postsynaptic maturation of synaptic transmission and plasticity of endbulb - Bushy Cell Synapses in the Cochlear Nucleus. J. Neurosci. 40, 2471–2484. doi: 10.1523/JNEUROSCI.2573-19.2020
9
ArmingolE.OfficerA. O.LewisN. E. (2021). Deciphering cell-cell interactions and communication from gene expression. Nat. Rev. Genet.22, 71–88. doi: 10.1038/s41576-020-00292-x
10
BaileyS. L.SchreinerB.McMahonE. J.MillerS. D. (2007). CNS myeloid DCs presenting endogenous myelin peptides 'preferentially' polarize CD4+TH17 cells in relapsing EAE. Nat. Immunol.8, 172–180. doi: 10.1038/ni1430
11
Bailey-BucktroutS. L.CaulkinsS. C.GoingsG.FischerJ. A. A.DzionekA.MillerS. D.et al. (2008). Central nervous system pDC dendritic cells regulate the severity of relapsing experimental autoimmune encephalomyelitis. J. Immunol.180, 6457–6461. doi: 10.4049/jimmunol.180.10.6457
12
BankeT. G.SchousboeA.PickeringD. S. (1997). Comparison of the agonist binding site of homomeric, heteromeric, and chimeric GluR1(0) and GluR3(0) AMPA receptors. J. Neurosci. Res.49, 176–185. doi: 10.1002/(sici)1097-4547(19970715)49:2<176::aid-jnr6>3.0.co;2-6
13
BaranovicJ. (2021). AMPA receptors in the synapse: very little space and even less time. Neuropharmacology196:108711. doi: 10.1016/j.neuropharm.2021.108711
14
BeggiatoS.BrownP. L.MilosavljevicS.ThomasM. A. R.PiroliM. V.SathyasaikumarK. V.et al. (2025). Functional impairments in learning and signal propagation following prenatal kynurenine treatment in mice. Eur. J. Neurosci.62:e70185. doi: 10.1111/ejn.70185
15
BelladonnaM. L.VolpiC.BianchiR.VaccaC.OrabonaC.PallottaM. T.et al. (2008). Cutting edge: autocrine TGF-β sustains default tolerogenesis by IDO-competent dendritic cells. J. Immunol.181, 5194–5198. doi: 10.4049/jimmunol.181.8.5194
16
BenussiA.AlbericiA.BurattiE.GhidoniR.GardoniF.Di LucaM.et al. (2019). Toward a glutamate hypothesis of frontotemporal dementia. Front. Neurosci.13:304. doi: 10.3389/fnins.2019.00304
17
BereczkiE.BrancaR. M.FrancisP. T.PereiraJ. B.BaekJ. H.HortobágyiT.et al. (2018). Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain141, 582–595. doi: 10.1093/brain/awx352
18
Berlinguer-PalminiR.MasiA.NarducciR.CavoneL.MarateaD.CozziA.et al. (2013). GPR35 activation reduces Ca2+ transients and contributes to the kynurenic acid-dependent reduction of synaptic activity at CA3-CA1 Synapses. PLoS ONE8:e82180. doi: 10.1371/journal.pone.0082180
19
BhandageA. K.JinZ.HellgrenC.KorolS. V.NowakK.WilliamssonL.et al. (2017). AMPA, NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women. J. Neuroimmunol. 305, 51–58. doi: 10.1016/j.jneuroim.2017.01.013
20
BonnetC.LeheupB.BeriM.PhilippeC.GregoireM.-J.JonveauxP.et al. (2009). Aberrant GRIA3 transcripts with multi-exon duplications in a family with X-Linked mental retardation. Amer. J. Med. Genetics149A, 1280–1289. doi: 10.1002/ajmg.a.32858
21
BorroniB.StanicJ.VerpelliC.MelloneM.BonomiE.AlbericiA.et al. (2017). Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target. Sci. Rept. 7:6723. doi: 10.1038/s41598-017-06117-y
22
BossuP.SpallettaG.CaltagironeC.CiaramellaA. (2015). Myeloid dendritic cells are potential players in human neurodegenerative diseases. Front. Immunol.6:632. doi: 10.3389/fimmu.2015.00632
23
BrownA. S. (2011a). The environment and susceptibility to schizophrenia. Progr. Neurobiol. 93, 23–58. doi: 10.1016/j.pneurobio.2010.09.003
24
BrownA. S. (2011b). Further evidence of infectious insults in the pathogenesis and pathophysiology of schizophrenia. Am. J. Psychiat. 168, 764–766. doi: 10.1176/appi.ajp.2011.11050722
25
BrownA. S.PattersonP. H. (2011). Maternal infection and schizophrenia: implications for prevention. Schizophrenia Bull.37, 284–290. doi: 10.1093/schbul/sbq146
26
BrownR.KabaniK.FavaloroJ.YangS.HoP. J.GibsonJ.et al. (2012a). CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis. Blood120, 2055–2063. doi: 10.1182/blood-2012-03-416792
27
BrownR.SuenH.FavaloroJ.YangS. H.HoP. J.GibsonJ.et al. (2012b). Trogocytosis generates acquired regulatory T cells adding further complexity to the dysfunctional immune response in multiple myeloma. Oncoimmunology1, 1658–1660. doi: 10.4161/onci.22032
28
BuckS. A.BarattaA. M.PocivavsekA. (2020). Exposure to elevated embryonic kynurenine in rats: sex-dependent learning and memory impairments in adult offspring Neurobiol. Learn. Memory174:107282. doi: 10.1016/j.nlm.2020.107282
29
CathomasF.HoltL. M.PariseE. M.LiuJ.MurroughJ. W.CasacciaP.et al. (2022). Beyond the neuron: role of non-neuronal cells in stress disorders. Neuron110, 1116–1138. doi: 10.1016/j.neuron.2022.01.033
30
CauwelsA.Van LintS.RoggeE.VerheeA.Van Den EeckhoutB.PangS. R.et al. (2021). Targeting IFN activity to both B cells and plasmacytoid dendritic cells induces a robust tolerogenic response and protection against EAE. Sci. Rept. 11:21575. doi: 10.1038/s41598-021-00891-6
31
CellaM.FacchettiF.LanzavecchiaA.ColonnaM. (2000). Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent THI polarization. Nat. Immunol. 1, 305–310. doi: 10.1038/79747
32
ChaliseJ. P.PallottaM. T.NarendraS. C.CarlssonB.IaconoA.NamaleJ.et al. (2016). IDO1 and TGF-β Mediate Protective Effects of IFN-α in Antigen-Induced Arthritis. J. Immunol. 197, 3142 −3151. doi: 10.4049/jimmunol.1502125
33
CharreauB. (2021). Secretome and tunneling nanotubes: a multilevel network for long range intercellular communication between endothelial cells and distant cells. Int. J. Mol. Sci.22:7971. doi: 10.3390/ijms22157971
34
ChenS. W.ZhongX. S.JiangL. N.ZhengX. Y.XiongY. Q.MaS. J.et al. (2016). Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: a systematic review and meta-analysis. Behav. Brain Res.296, 61–69. doi: 10.1016/j.bbr.2015.08.035
35
ChenW.LiangX. Q.PetersonA. J.MunnD. H. Blazar B. R. (2008). The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J. Immunol.181, 5396–5404. doi: 10.4049/jimmunol.181.8.5396
36
ChenX.LiangH. W.ZhangJ. F.ZenK.ZhangC. Y. (2012). Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein Cell3, 28–37. doi: 10.1007/s13238-012-2003-z
37
ChiyonobuT.HayashiS.KobayashiK.MorimotoM.MiyanomaeY.NishimuraA.et al. (2007). Partial tandem duplication of GRIA3 in a male with mental retardation. Am. J. Med. Genet.143A, 1448–1455. doi: 10.1002/ajmg.a.31798
38
ClanchyF. I. L.WilliamsR. O.StoneT. W. (2026). Paradoxical expression of ionotropic glutamate receptors in leucocytes. Clin. Revs. Allergy Immunol. 69:19. doi: 10.1007/s12016-025-09126-2
39
ClarksonB. D.WalkerA.HarrisM.RayasamA.SandorM.FabryZ. (2014). Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE. J. Neuroimmunol.277, 39–49. doi: 10.1016/j.jneuroim.2014.09.016
40
CocucciE.MeldolesiJ. (2015). Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol.25, 364–372. doi: 10.1016/j.tcb.2015.01.004
41
ColemanS. K.HouY.WillibaldM.SemenovA.MöykkynenT.KeinänenK. (2016). Aggregation limits surface expression of homomeric GluA3 receptors. J. Biol. Chem. 291, 8784–8794. doi: 10.1074/jbc.M115.689125
42
ColemanS. K.MöykkynenT.CaiC. L.von OssowskiL.KuismanenE.KorpiE. R.et al. (2006). Isoform-specific early trafficking of AMPA receptor flip and flop variants. J. Neurosci.26, 11220–11229. doi: 10.1523/JNEUROSCI.2301-06.2006
43
ColemanS. K.MoykkynenT. S.VaahteraL.KorpiE. R.PentikainenO. T.et al. (2010). Ligand-binding domain determines endoplasmic reticulum exit of AMPA receptors. J. Biol. Chem.285, 36032–36039. doi: 10.1074/jbc.M110.156943
44
ColonnaM.TrinchieriG.LiuY. J. (2004). Plasmacytoid dendritic cells in immunity. Nat. Immunol.5, 1219–1226. doi: 10.1038/ni1141
45
CoumoulX.BaroukiR.EsserC.Haarmann-StemmannT.LawrenceB. P.LehmannJ.et al. (2026). The aryl hydrocarbon receptor: structure, signaling, physiology and pathology. Signal Transduct. Target. Therapy11:20. doi: 10.1038/s41392-025-02500-8
46
da SilvaJ. A. C.SchroederN. (2023). The Role of Ca2+ Permeable AMPA receptors in neurodegeneration, neurotoxicity, and neuroinflammation. CNS Neurol. Disord. Drug Targets22, 624–633. doi: 10.2174/1871527321666220510141735
47
DaviesB.BrownL. A.CaisO.WatsonJ.ClaytonA. J.ChangV. T.et al. (2017). A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability. Human Mol. Genet.26, 3869–3882. doi: 10.1093/hmg/ddx270
48
DavisD. M. (2007). Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response. Nat. Rev. Immunol. 7, 238–243. doi: 10.1038/nri2020
49
de BartolomeisA.FornaroM.ScopettaE.RicciC.IranoA.de SimoneG.et al. (2025). Chronic stress and brain kynurenine pathway: addressing unresolved issues with a meta-analytic approach of preclinical studies, translational implication for psychiatric disorders. Eur. Neuropsychopharmacol.101, 22–40. doi: 10.1016/j.euroneuro.2025.10.005
50
de Leon-LópezC. A. M.Carretero-ReyM.KhanZ. U. (2025). AMPA receptors in synaptic plasticity, memory function, and brain diseases. Cell Molec. Neurobiol.45:14. doi: 10.1007/s10571-024-01529-7
51
DengJ.JiY. H.ZhuF. J.LiuL. N.LiL. M.BaiX.et al. (2022). Mapping secretome-mediated interaction between paired neuron-macrophage single cells. Proc. Natl. Acad. Sci. U.S.A.119:e2200944119. doi: 10.1073/pnas.2200944119
52
DiehlF. K.ChotiM. A.RomansK.GoodmanS.LiM.ThorntonK.et al. (2008). Circulating mutant DNA to assess tumor dynamics. Nat. Med. 14, 985–990. doi: 10.1038/nm.1789
53
DieringG. H.HuganirR. L. (2018). The AMPA receptor code of synaptic plasticity. Neuron100, 314–329. doi: 10.1016/j.neuron.2018.10.018
54
DuraesF. V.LippensC.SteinbachK.DubrotJ.BrighouseD.Bendriss-VermareN.et al. (2016). pDC therapy induces recovery from EAE by recruiting endogenous pDC to sites of CNS inflammation. J. Autoimmun. 67, 8–18. doi: 10.1016/j.jaut.2015.08.014
55
DuricV.BanasrM.StockmeierC. A.SimenA. A.NewtonS. S.OverholserJ. C.et al. (2013). Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int. J. Neuropsychopharmacol. 16, 69–82. doi: 10.1017/S1461145712000016
56
EkströmK.ValadiH.SjöstrandM.MalmhällC.BossiosA.EldhM.et al. (2012). Characterization of mRNA and microRNA in human mast cell-derived exosomes and their transfer to other mast cells and blood CD34 progenitor cells. J. Extracell. Vesicles1:18389. doi: 10.3402/jev.v1i0.18389
57
EmamalipourM.SeidiK.VahedZ.Jahanban-EsfahlanA.JaymandM.MajdiH.et al. (2020). Horizontal gene transfer: from evolutionary flexibility to disease progression. Front. Cell Devel. Biol. 8:229. doi: 10.3389/fcell.2020.00229
58
EnacheD.PereiraJ. B.JelicV.WinbladB. P.NilssonP.AarslandD.et al. (2020). Increased cerebrospinal fluid concentration of ZnT3 is associated with cognitive impairment in Alzheimer's disease. J. Alzheimer's Dis.77, 1143–1155. doi: 10.3233/JAD-200498
59
ErhardtS.SchwielerL.ImbeaultS.EngbergG. (2017). The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology112, 297–306. doi: 10.1016/j.neuropharm.2016.05.020
60
FacchettiF.De Wolf-PeetersC.van den OordJ. J. (1988b). Plasmacytoid T cells: a cell population normally present in the reactive lymph node. An immunohistochemical and electronmicroscopic study. Human Pathol. 19, 1085–1092. doi: 10.1016/S0046-8177(88)80091-1
61
FacchettiF.de Wolf-PeetersC. Mason D. Y. (1988a). Plasmacytoid T cells. Imunohistochemical evidence for their monocyte/macrophage origin. Am. J. Pathol.133, 15–21.
62
ForrestC. M.KhalilO. S.PisarM.DarlingtonL. G.StoneT. W. (2013a). Prenatal inhibition of the tryptophan- kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus. Brain Res. 1504, 1–15. doi: 10.1016/j.brainres.2013.01.031
63
ForrestC. M.KhalilO. S.PisarM.McNairK.KornisiukE.SnitcofskyM.et al. (2013b). Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway. Neuroscience254, 241–259. doi: 10.1016/j.neuroscience.2013.09.034
64
FukushimaK.HatanakaK.SaganeK.IdoK. (2020). Inhibitory effect of anti-seizure medications on ionotropic glutamate receptors: special focus on AMPA receptor subunits. Epilepsy Res.167:106452. doi: 10.1016/j.eplepsyres.2020.106452
65
FurmanD.CampisiJ.VerdinE.Carrera-BastosP.TargS.FranceschiC.et al. (2019). Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832. doi: 10.1038/s41591-019-0675-0
66
GallizioliM. F.Otxoa-de-AmezagaA.CugotaR.Salas-PerdomoA.JusticiaC.et al. (2020). Dendritic cells and microglia have non-redundant functions in the inflamed brain with protective effects of type 1 cDCs. Cell Rep.33:108291. doi: 10.1016/j.celrep.2020.108291
67
GeY.WangY. T. (2021). GluA1-homomeric AMPA receptor in synaptic plasticity and neurological diseases. Neuropharmacology197:108708. doi: 10.1016/j.neuropharm.2021.108708
68
GeczJ.BarnettS.LiuJ. J.HollwayG.DonnellyA.EyreH.et al. (1999). Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation. Genomics 62, 356–368. doi: 10.1006/geno.1999.6032
69
GilesD. A.DunckerP. C.WilkinsonN. M.Washnock-SchmidJ. M.SegalB. M. (2018). CNS-resident classical DCs play a critical role in CNS autoimmune disease. J Clin. Invest. 128, 5322–5334. doi: 10.1172/JCI123708
70
GirchenkoP.Lahti-PulkkinenM.HeinonenK.ReynoldsR. M.LaivuoriH.LipsanenJ.et al. (2020). Persistently high levels of maternal antenatal inflammation are associated with and mediate the effect of prenatal environmental adversities on neurodevelopmental delay in the offspring. Biol. Psychiat.87, 898–907. doi: 10.1016/j.biopsych.2019.12.004
71
GregerI. H.WatsonJ. F.Cull-CandyS. G. (2017). Structural and functional architecture of AMPA-type glutamate receptors and their auxiliary proteins. Neuron94, 713–730. doi: 10.1016/j.neuron.2017.04.009
72
GrocL.ChoquetD. (2006). AMPA and NMDA glutamate receptor trafficking: multiple roads for reaching and leaving the synapse. Cell Tissue Res.326, 423–438. doi: 10.1007/s00441-006-0254-9
73
GuilmatreA.DubourgC.MoscaA. L.LegallicS.GoldenbergA.Drouin-GarraudV.et al. (2009). Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch. Gen. Psych. 66, 947–950. doi: 10.1001/archgenpsychiatry.2009.80
74
Gutierrez-CastellanosN.Da Silva-MatosC. M.ZhouK.CantoC. B.RennerM. C.KoeneL. M. C.et al. (2017). Motor learning requires purkinje cell synaptic potentiation through activation of AMPA-Receptor Subunit GluA3. Neuron93, 409–424. doi: 10.1016/j.neuron.2016.11.046
75
HamanakaK. (2022). Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant. Human Genet.141, 283–293. doi: 10.1007/s00439-021-02416-7
76
HansenK. B.WollmuthL. P.BowieD.FurukawaH.MennitiF. S.SobolevskyA.et al. (2021). Structure, function, and pharmacology of glutamate receptor ion channels. Pharmacol. Rev. 73, 298–487. doi: 10.1124/pharmrev.120.000131
77
HenleyJ. M.WilkinsonK. A. (2016). Synaptic AMPA receptor composition in development, plasticity and disease. Nat. Rev. Neurosci. 17, 337–350. doi: 10.1038/nrn.2016.37
78
HennegriffM.AraiA.KesslerM.VanderklishP.MutnejaM. S.RogersG.et al. (1997). Stable expression of recombinant AMPA receptor subunits: binding affinities and effects of allosteric modulators. J. Neurochem.68, 2424–2434. doi: 10.1046/j.1471-4159.1997.68062424.x
79
HenryJ. E.FinebergA. A.McVeyT. B.TiemeierE. L.OrfilaJ. E.HersonP. S.et al. (2026). Delayed administration of type II ampakines enhance synaptic plasticity and cognitive recovery in juvenile global cerebral ischemia J. Cereb. Blood Flow Metab.46, 1681–1692. doi: 10.1177/0271678X251405662
80
HernandezA. F.DiamondB.LiaoJ.MarchA. N.KesterK. E. (2026). Seeing the forest through the trees: harmonizing Infection-Associated Chronic Illnesses research (IACI). Proc. Nat. Acad. Sci. U.S.A.123:e2600628123. doi: 10.1073/pnas.2600628123
81
HiranoT. (2018). Visualization of Exo- and Endocytosis of AMPA receptors during hippocampal synaptic plasticity around postsynaptic-like membrane formed on glass surface. Front. Cell. Neurosci. 12:442. doi: 10.3389/fncel.2018.00442
82
HolleyS. M.AhmedA. H.SrinivasanJ.MurthyS. E.WeilandG. A.OswaldR. E.et al. (2012). The loss of an electrostatic contact unique to AMPA receptor ligand NBQX binding domain 2 slows channel activation. Biochemistry51, 4015–4027. doi: 10.1021/bi3001837
83
HornigM.BresnahanM. A.CheX.SchultzA. F.UkaigweJ. E.EddyM. L.et al. (2018). Prenatal fever and autism risk. Molec. Psychiat. 23, 759–766. doi: 10.1038/mp.2017.119
84
HoyeM. L.ArchambaultA. S.GordonT. M.OetjenL. K.CainM. D.KleinR. S.et al. (2018). MicroRNA signature of central nervous system-infiltrating dendritic cells in an animal model of multiple sclerosis. Immunology155, 112–122. doi: 10.1111/imm.12934
85
HuM. J.LongM.DaiR. J. (2022). Acetylation of H3K27 activated lncRNA NEAT1 and promoted hepatic lipid accumulation in non-alcoholic fatty liver disease via regulating miR-212-5p/GRIA3. Mol. Cell. Biochem.477, 191–203. doi: 10.1007/s11010-021-04269-0
86
HuangX.YuanT.TschannenM.SunZ.JacobH.DuM.et al. (2013). Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics14:319. doi: 10.1186/1471-2164-14-319
87
HuangX. B.DingW. H.WuF. C.ZhouS. M.DengS. H.NingY. P. (2020). Increased plasma kynurenic acid levels are associated with impaired attention/vigilance and social cognition in patients with schizophrenia. Neuropsych. Dis. Treatment16, 263–271. doi: 10.2147/NDT.S239763
88
HuangY.-S.OgbechiJ.ClanchyF. I. L.WilliamsR. O.StoneT. W. (2020). Kynurenine metabolites in peripheral disorders and neuroinflammation. Front. Immunol.11:388. doi: 10.3389/fimmu.2020.00388
89
HuganirR. L.NicollR. A. (2013). AMPARs and synaptic plasticity: the last 25 years. Neuron80, 704–717. doi: 10.1016/j.neuron.2013.10.025
90
HumeauY.ReiselD.JohnsonA. W.BorchardtT.JensenV.GebhardtC.et al. (2007). A pathway-specific function for different AMPA receptor subunits in amygdala long-term potentiation and fear conditioning. J. Neurosci. 27, 10947–10956. doi: 10.1523/JNEUROSCI.2603-07.2007
91
IamjanS.ThanoiS.WatiktinkornP.ReynoldsG. P.Nudmamud-ThanoiS. (2018). Genetic variation of GRIA3 gene is associated with vulnerability to methamphetamine dependence and its associated psychosis. J. Psychopharmacol.32, 309–315. doi: 10.1177/0269881117750153
92
ItaliaM.FerrariE.Di LucaM.GardoniM. F. (2021). GluA3-containing AMPA receptors: from physiology to synaptic dysfunction in brain disorders. Neurobiol. Dis. 161:105539. doi: 10.1016/j.nbd.2021.105539
93
ItaliaM.FerrariE.DiLucaM.GardoniF. (2022). NMDA and AMPA receptors at synapses: novel targets for Tau and α-Synuclein proteinopathies. Biomedicines10:1550. doi: 10.3390/biomedicines10071550
94
ItaliaM.SalvadeM.La GrecaF.ZianniE.PelucchiS.SpinolaA.et al. (2024). Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features. Brain Behav. Immun.118, 380–397. doi: 10.1016/j.bbi.2024.03.018
95
JacobA. L.WeinbergR. J. (2015). The organization of AMPA receptor subunits at the postsynaptic membrane. Hippocampus25, 798–812. doi: 10.1002/hipo.22404
96
JahanS.MukherjeeS.AliS.BhardwajU.ChoudharyR. K.BalakrishnanS.et al. (2022). Pioneer role of extracellular vesicles as modulators of cancer initiation in progression, drug therapy, and vaccine prospects. Cells11:490. doi: 10.3390/cells11030490
97
JegalianA. G.FacchettiF.JaffeE. S. (2009). Plasmacytoid dendritic cells: physiologic roles and pathologic states. Adv. Anat. Pathol, 16, 392–404. doi: 10.1097/PAP.0b013e3181bb6bc2
98
JiaZ.CollingridgeG. L. (2017). Learning about Synaptic GluA3. Neuron93, 254–256. doi: 10.1016/j.neuron.2017.01.004
99
JiangL.WangM.LinS.JianR.LiX.ChanJ.et al. (2020). A quantitative proteome map of the human body. Cell183, 269–283. doi: 10.1101/797373
100
JiangP.LoY. M. (2016). The long and short of circulating cell-free DNA and the ins and outs of molecular diagnostics. Trends Genet.32, 360–371. doi: 10.1016/j.tig.2016.03.009
101
JonesK. L.CroenL. A.YoshidaC. K.HeuerL.HansenR.ZerboO.et al. (2017). Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol. Psychiat. 22, 273–279. doi: 10.1038/mp.2016.77
102
KakegawaW.TsuzukiK.YoshidaY.KameyamaK.OzawaS. (2004). Input- and subunit-specific AMPA receptor trafficking underlying long-term potentiation at hippocampal CA3 synapses. Eur. J. Neurosci.20, 101–110. doi: 10.1111/j.1460-9568.2004.03461.x
103
KamyshnaI. I.PavlovychL. B.KamyshnyiA. M. (2022). NMDA gene polymorphism (rs4880213) and GRIN2B blood serum levels in thyroid pathology patients. J. Med. Life15, 109–116. doi: 10.25122/jml-2021-0372
104
KeelingP. J.PalmerJ. D. (2008). Horizontal gene transfer in eukaryotic evolution. Nat. Rev. Genet.9, 605–618. doi: 10.1038/nrg2386
105
KegelM. E.JohanssonV.WetterbergL.BhatM.SchwielerL.CannonT. D.et al. (2017). Kynurenic acid and psychotic symptoms and personality traits in twins with psychiatric morbidity. Psychiat. Res.247, 105–112. doi: 10.1016/j.psychres.2016.11.017
106
KhalilO. S.PisarM.ForrestC. M.VincentenM. C. J.DarlingtonL. G. Stone T. W. (2014). Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring. Eur. J. Neurosci. 39, 1558–1571. doi: 10.1111/ejn.12535
107
KindlerJ.LimC. K.WeickertC. S.BoerrigterD.GalletlyC.LiuD.et al. (2020). Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia. Molec. Psychiat.25, 2860–2872. doi: 10.1038/s41380-019-0401-9
108
KipnisJ. (2016). Multifaceted interactions between adaptive immunity and the CNS. Science353, 766–771. doi: 10.1126/science.aag2638
109
KipnisJ.CohenH.CardonM.ZivY.SchwartzM. (2004). T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Nat. Acad. Sci. U.S.A.101, 8180–8185. doi: 10.1073/pnas.0402268101
110
KozakR.CampbellE. M.StrickC. A.HornerW.HoffmannW. E.KissT.et al. (2014). Reduction of brain kynurenic acid improves cognitive function. J. Neurosci.34, 10592–10602. doi: 10.1523/JNEUROSCI.1107-14.2014
111
KrakowiakP.WalkerC. K.BremerA. A.BakerA. S.OzonoffS.HansenR. L.et al. (2012). Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics129, e1121–e1128. doi: 10.1542/peds.2011-2583
112
KristensenA. S.JenkinsM. A.BankeT. G.SchousboeA.MakinoY.JohnsonR. C.et al. (2011). Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating. Nat. Neurosci. 14, 727–735. doi: 10.1038/nn.2804
113
LannaA.VazB.D'AmbraC.ValvoS.VuottoC.ChiurchiuV.et al. (2022). An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory. Nat. Cell Biol. 24, 1461–1474. doi: 10.1038/s41556-022-00991-z
114
Lehmann-WermanR.NeimanD.ZemmourH.MossJ.MagenheimJ.Vaknin-DembinskyA.et al. (2016). Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc. Natl. Acad. Sci. U.S.A.113, E1826–E1834. doi: 10.1073/pnas.1519286113
115
LeoA.GiovanniniG.RussoE.MelettiS. (2018). The role of AMPA receptors and their antagonists in status epilepticus. Epilepsia59, 1098–1108. doi: 10.1111/epi.14082
116
LiQ. S.HardenJ. L.AndersonC. D.EgilmezN. K. (2016). Tolerogenic phenotype of IFN-gamma-induced IDO+ dendritic cells is maintained via an autocrine IDOkynurenine/ AhR-IDO loop. J. Immunol. 197, 962–970. doi: 10.4049/jimmunol.1502615
117
LiS.WuJ.ZhuS.LiuY. J.ChenJ. (2017). Disease-associated plasmacytoid dendritic cells. Front. Immunol.16:1268. doi: 10.3389/fimmu.2017.01268
118
LiM.ZeringerE.BartaT.ShagemanJ.ChengA. G.VlassovA. V. (2014). Analysis of the RNA content of the exosomes derived from blood serum and urine and its potential as biomarkers. Phil. Trans. Roy. Soc.369:AR.201350502. doi: 10.1098/rstb.2013.0502
119
LimonA.Reyes-RuizJ. M.EusebiF.MilediR. (2007). Properties of GluR3 receptors tagged with GFP at the amino or carboxyl terminus. Proc. Nat. Acad. Sci. U.S.A.104, 15526–15530. doi: 10.1073/pnas.0706773104
120
LippensC.DuraesF. V.DubrotJ.BrighouseD.LacroixM.IrlaM.et al. (2016). IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity. J. Autoimmunity75, 39–49. doi: 10.1016/j.jaut.2016.07.004
121
LitzenburgerU. M.OpitzC. A.SahmF.RauschenbachK. J.TrumpS.WinterM.et al. (2014). Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget5, 1038–1051. doi: 10.18632/oncotarget.1637
122
LiuH.RamachandranI.GabrilovichD. I. (2014). Regulation of plasmacytoid dendritic cell development in mice by aryl hydrocarbon receptor. Immunol. Cell Biol. 92, 200–203. doi: 10.1038/icb.2013.65
123
LunavatT. R.ChengL.KimD. K.BhaduryJ.JangS.C.LässerR. A.et al. (2015). Small RNA deep sequencing discriminates subsets of extracellular vesicles released by melanoma cells–Evidence of unique microRNA cargos. RNA Biol.12, 810–23. doi: 10.1080/15476286.2015.1056975
124
LynchG.GallC. M. (2006). Ampakines and the threefold path to cognitive enhancement. Trends Neurosci.29, 554–562. doi: 10.1016/j.tins.2006.07.007
125
MacDonaldM. L.YingD.NewmanJ.HembyS. P.LewisD. A.et al. (2015). Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. Biol. Psychiat. 77, 959–968. doi: 10.1016/j.biopsych.2014.09.006
126
MagriC.GardellaR. P.ValsecchiP.BarlatiS. D.GuizzettiL.ImperadoriL.et al. (2008). Study on GRIA2, GRIA3 and GRIA4 genes highlights a positive association between schizophrenia and GRIA3 in female patients. Amer. J. Med. Genetics Part B147B, 745–753. doi: 10.1002/ajmg.b.30674
127
MaherB. H.LeaR. A. J.CoxH. C.FernandezF.EspositoT.et al. (2013). Association of a GRIA3 gene polymorphism with migraine in an Australian case-control cohort. Headache53, 1245–1249. doi: 10.1111/head.12151
128
MalinaK. C. K.GanorY.LeviteM.TeichbergV. I. (2006). Autoantibodies against an extracellular peptide of the GluR3 subtype of AMPA receptors activate both homomeric and heteromeric AMPA receptor channels. Neurochem. Res. 31, 1181–1190. doi: 10.1007/s11064-006-9143-6
129
ManH. Y.JuW.AhmadianG. Y. T. (2000a). Intracellular trafficking of AMPA receptors in synaptic plasticity. Cell. Molec. Life Sci. 57, 1526–1534. doi: 10.1007/PL00000637
130
ManH. Y.LinJ. W.JuW. H.AhmadianG.LiuL. D.BeckerL. E.et al. (2000b). Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron25, 649–662. doi: 10.1016/S0896-6273(00)81067-3
131
MeenaM.Van DelenM.De LaereM.SterkensA.RomeroC. C.BernemanZ.et al. (2021). Transmigration across a steady-state blood-brain barrie induces activation of circulating dendritic cells partly mediated by actin cytoskeletal reorganization. Membranes11:700. doi: 10.3390/membranes11090700
132
MelnikovaA. M. E.PijuanJ.AparicioJ.RamírezA.Altisent-HuguetA. A.et al. (2022). The p.Glu787Lys variant in the GRIA3 gene causes developmental and epileptic encephalopathy mimicking structural epilepsy in a female patient. Eur. J. Med. Gen.65:104442. doi: 10.1016/j.ejmg.2022.104442
133
MengY. H.ZhangY.JiaZ. P. (2003). Synaptic transmission and plasticity in the absence of AMPA glutamate receptor GluR2 and GluR3. Neuron39, 163–176. doi: 10.1016/S0896-6273(03)00368-4
134
MeserveyL. M.TopkarV. V.FuM. M. (2021). mRNA transport and local translation in Glia. Trends Cell Biol.31, 419–423. doi: 10.1016/j.tcb.2021.03.006
135
MeyerU.FeldonJ. (2010). Epidemiology-driven neurodevelopmental animal models of schizophrenia. Progr. Neurobiol. 90, 285–326. doi: 10.1016/j.pneurobio.2009.10.018
136
MeyerU.NyffelerM.YeeB. K.KnueselI.FeldonJ. (2008). Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav. Immun. 22, 469–486. doi: 10.1016/j.bbi.2007.09.012
137
MilhamL. T.MorrisG. P.KonenL. M.RentschP.AvganN.VisselB. (2024). Quantification of AMPA receptor subunits and RNA editing-related proteins in the J20 mouse model of Alzheimer's disease by capillary western blotting. Front. Molec. Neurosci. 16:1338065. doi: 10.3389/fnmol.2023.1338065
138
MithaiwalaM. N.Santana-CoelhoD.PorterG. A.O'ConnorJ. C. (2021). Neuroinflammation and the kynurenine pathway in CNS disease: molecular mechanisms and therapeutic implications. Cells10:1548. doi: 10.3390/cells10061548
139
MiyakeK.KarasuyamaH. (2021). The role of trogocytosis in the modulation of immune cell functions. Cells10:1255. doi: 10.3390/cells10051255
140
MorettoE.MurruL.MartanoG.SassoneJ.PassafaroM. (2018). Glutamatergic synapses in neurodevelopmental disorders. Prog. Neuropsychopharmacol. Biol. Psychiat. 84, 328–342. doi: 10.1016/j.pnpbp.2017.09.014
141
MundtS.GreterM.FlügelA.BecherB. (2019). The CNS immune landscape from the viewpoint of a T cell. Trends Neurosci. 42, 667–679. doi: 10.1016/j.tins.2019.07.008
142
NakanishiN.ShneiderN. A.AxelR. (1990). A family of glutamate receptor genes: evidence for the formation of heteromultimeric receptors with distinct channel properties. Neuron5, 569–581. doi: 10.1016/0896-6273(90)90212-X
143
NakayamaM.HoriA.ToyouraS.YamaguchiS. I. (2021). Shaping of T cell functions by trogocytosis. Cells10:1155. doi: 10.3390/cells10051155
144
NecpálJ.WinkelmannJ. M.JechR. (2023). A de novo GRIA3 variant with complex hyperkinetic movement disorder in a girl with developmental delay and self-limited epilepsy. Parkinsonism Relat. Disord.111:105437. doi: 10.1016/j.parkreldis.2023.105437
145
Nevarez-RamirezA. J.Guzman-OrtizA. L.Cortes-ReynosaP.Perez-SalazarE.Jaimes-OrtegaG. A.Valle-RiosR.et al. (2023). Shotgun proteomics of co-cultured leukemic and bone marrow stromal cells from different species as a preliminary approach to detect intercellular protein transfer. Proteomes11:15. doi: 10.3390/proteomes11020015
146
NeveR. L.HoweJ. R.HongS.KalbR. G. (1997). Introduction of the glutamate receptor subunit 1 into motor neurons in vitro and in vivo using a recombinant herpes simplex virus. Neuroscience79, 435–447. doi: 10.1016/S0306-4522(96)00645-8
147
NewpherT. M.EhlersM. D. (2008). Glutamate receptor dynamics in dendritic microdomains. Neuron58, 472–497. doi: 10.1016/j.neuron.2008.04.030
148
NielsenB. S.BankeT. G.SchousboeA. D. S. (1998). Pharmacological properties of homomeric and heteromeric GluR1o and GluR3o receptors. Europ. J. Pharmacol.360, 227–238. doi: 10.1016/S0014-2999(98)00668-2
149
NingL. Y.ShenR. J.XieB. Q.JiangY.GengX. Q.DongW. l. (2024). AMPA receptors in Alzheimer disease: pathological changes and potential therapeutic targets. J. Neuropathol. Exp. Neurol.83, 895–906. doi: 10.1093/jnen/nlae093
150
NishimuraS.IizukaM.WakamoriM.AkibaI. K.BarsoumianE. L. (2000). Stable expression of human homomeric and heteromeric AMPA receptor subunits in HEK293 cells. Recept. Channels7, 139–150.
151
NishiyamaA.SatoM.KimuraM.KatakuraA.TazakiM.ShibukawaY.et al. (2016). Intercellular signal communication among odontoblasts and trigeminal ganglion neurons via glutamate. Cell Calcium60, 341–355. doi: 10.1016/j.ceca.2016.07.003
152
O'BrienK.BreyneK.UghettoS.LaurentL. C.BreakefieldX. O. (2020). RNA delivery by extracellular vesicles in mammalian cells and its applications. Nat. Rev. Molec. Cell Biol. 21, 585–606. doi: 10.1038/s41580-020-0251-y
153
O'ConnorJ. A.HembyS. E. (2007). Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia. Schizophrenia Res. 97, 277–288. doi: 10.1016/j.schres.2007.09.022
154
OkanoS.MakitaY.MiyamotoA.TaketazuG.KimuraK. I.et al. (2023). GRIA3 p.Met661Thr variant in a female with developmental epileptic encephalopathy. Human Genome Var.10:4. doi: 10.1038/s41439-023-00232-1
155
OpitzC. A.LitzenburgerU. M.SahmF.OttM.TritschlerI.TrumpS.et al. (2011). An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature478, 197–203. doi: 10.1038/nature10491
156
OrhanF.MalwadeS.KshanhlarkhaniN.GkogkaA. Langeder A JungholmO.et al. (2025). Kynurenic acid and promotion of activity-dependent synapse elimination in schizophrenia. Amer. J. Psychiat. 182, 389–400. doi: 10.1176/appi.ajp.20240048
157
PaleseF.BonomiE.NuzzoT.BenussiA.MelloneM.ZianniE.et al. (2020). Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure. Neurobiol. Aging 86, 143–155. doi: 10.1016/j.neurobiolaging.2019.10.015
158
PallottaM. T.OrabonaC.VolpiC.VaccaC.BelladonnaM. L.BianchiR.et al. (2011). Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nature Immunol.12, 870–878. doi: 10.1038/ni.2077
159
PaolicelliR. C.GergaminiG.RajendranL. (2019). Cell-to-cell communication by extracellular vesicles: focus on microglia. Neuroscience405, 148–157. doi: 10.1016/j.neuroscience.2018.04.003
160
ParkY.JangC. G.YangK. H.LohH. H.MaT. E.HoI. K. (2003). Regional specific increases of [3H]AMPA binding and mRNA expression of AMPA receptors in the brain of μ-opioid receptor knockout mice. Molec. Brain Res. 113, 116–123. doi: 10.1016/S0169-328X(03)00123-2
161
PayandehZ. B.SynnergrenJ.Heydarkhan-HagvallS.NordinJ. Z.AndaloussiS. E.et al. (2024). Extracellular vesicles transport RNA between cells: unraveling their dual role in diagnostics and therapeutics. Molec. Aspects Med.99:101302. doi: 10.1016/j.mam.2024.101302
162
PearceB. D. (2003). Modeling the role of infections in the etiology of mental illness. Clin. Neurosci. Res. 3, 271–282. doi: 10.1016/S1566-2772(03)00098-7
163
PeiW. M.HuangZ.NiuL. (2007). GluR3 flip and flop: differences in channel opening kinetics. Biochemistry46, 2027–2036. doi: 10.1021/bi062213s
164
PeiW. M.HuangZ.WangC.HanY.ParkJ. S.NiuL. (2009). Flip and flop: a molecular determinant for AMPA receptor channel opening. Biochemistry48, 3767–777. doi: 10.1021/bi8015907
165
PengS. X.PeiJ.RinaldiB.ChenJ.GeY. H.JiaM.et al. (2022). Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human. Mol. Psychiatry27, 4092–4102. doi: 10.1038/s41380-022-01659-8
166
PennellL. M.FishE. N. (2017). Interferon-β regulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis. Immunology152, 439–450. doi: 10.1111/imm.12781
167
PerkinsM. N.StoneT. W. (1982). An iontophoretic investigation of the action of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res.247, 184–187. doi: 10.1016/0006-8993(82)91048-4
168
PerversiF.CostaC.LabateA.LattanziS.LiguoriC.MaschioM.et al. (2023). The broad-spectrum activity of perampanel: state of the art and future perspective of AMPA antagonism beyond epilepsy. Front. Neurol. 14:1182304. doi: 10.3389/fneur.2023.1182304
169
PetersJ. J.LeitzJ.Oses-PrietoJ. A.BurlingameA. L.BrungerA. T. (2021). Molecular characterization of AMPA-receptor-containing vesicles. Front. Molec. Neurosci. 14:754631. doi: 10.3389/fnmol.2021.754631
170
PiardJ.BereauM.XiangWeiW.WirthT.AmsallemD.BuissonL.et al. (2020). The GRIA3 c.2477G > A Variant causes an exaggerated startle reflex, chorea, and multifocal myoclonus. Movement Disord.35, 1224–1232. doi: 10.1002/mds.28058
171
PisarM.ForrestC. M.KhalilO. S.McNairK.VincentenM. C. J.QasemS.et al. (2014). Modified neocortical and cerebellar protein expression and morphology following prenatal inhibition of the kynurenine pathway. Brain Res.1576, 1–17. doi: 10.1016/j.brainres.2014.06.016
172
PokharnaA.StockwellI.IvicaJ.SinghB.SchwabJ. C.Vega-GutiérrezC.et al. (2025). Architecture, dynamics and biogenesis of GluA3 AMPA glutamate receptors. Nature645, 535–540. doi: 10.1038/s41586-025-09325-z
173
PoonK.NowakL. M.OswaldR. E. (2010). Characterizing single-channel behavior of GluA3 receptors. Biophysical J.99, 1437–1446. doi: 10.1016/j.bpj.2010.06.058
174
PrinkeyK.ThompsonE.SaikiaJ.CidT.DoreK. (2024). Fluorescence lifetime imaging of AMPA receptor endocytosis in living neurons: effects of Aβ and PP1. Front. Molec. Neurosci.2024:1409401. doi: 10.3389/fnmol.2024.1409401
175
PuccettiP.FallarinoF. (2008). Generation of T cell regulatory activity by plasmacytoid dendritic cells and tryptophan metabolism. Blood Cells Mol. Dis.40, 101–105. doi: 10.1016/j.bcmd.2007.06.026
176
RaiA.FangH. Y.ClaridgeB.SimpsonR. J.GreeningD.W. (2021a). Proteomic dissection of large extracellular vesicle surfaceome unravels interactive surface platform. J. Extracellular Vesicles10:e12164. doi: 10.1002/jev2.12164
177
RaiA.GreeningD. W.XuR.ChenM.SuwakulsiriW.SimpsonR. J.et al. (2021b). Secreted midbody remnants are a class of extracellular vesicles molecularly distinct from exosomes and microparticles. Commun. Biol. 4:400. doi: 10.1038/s42003-021-01882-z
178
RazaM. L.FatimaM.RawaliaM. A.RazaR. (2016). A narrative review on exosomes therapeutics in stroke: advancing neuroprotection and regeneration. Proc. Nat Acad. Sci.113, E6526–E6534. doi: 10.1073/pnas.1614249113
179
ReedJ.ReicheltM.WetzelS. A. (2021). Lymphocytes and trogocytosis-mediated signaling. Cells10:1478. doi: 10.1016/j.neuroscience.2025.08.044
180
ReindersN. R.van der SpekS. J. F.KlaassenR. V.KoymansK. J.MacgillavryH. D.SmitA. B.et al. (2016). Amyloid-beta effects on synapses and memory require AMPA receptor subunit GluA3. Proc. Natl. Acad. Sci. U.S.A.113, E6526–E6534.
181
ReizisB. (2019). Plasmacytoid dendritic cells: development, regulation, and function. Immunity50, 37–50. doi: 10.1016/j.immuni.2018.12.027
182
RektorI. (2013). Perampanel, a novel, non-competitive, selective AMPA receptor antagonist as adjunctive therapy for treatment-resistant partial-onset seizures. Expert Opin. Pharmacotherapy14, 225–235. doi: 10.1517/14656566.2013.754883
183
RennerM. C.AlbersE. H. H.Gutierrez-CastellanosN.ReindersN. R.van HuijsteeA. N.XiongH.et al. (2017). Synaptic plasticity through activation of GluA3-containing AMPA-receptors. ELIFE6:e25462. doi: 10.7554/eLife.25462.023
184
RestaF.MasiA.SiliM.LaurinoA.MoroniF.MannaioniG. (2016). Kynurenic acid and zaprinast induce analgesia by modulating HCN channels through GPR35 activation. Neuropharmacology108, 136–143. doi: 10.1016/j.neuropharm.2016.04.038
185
RidderK.KellerS.DamsM.RuppA. K.SchlaudraffJ.Del TurcoD.et al. (2014). Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation. PLoS Biol.12:e1001874. doi: 10.1371/journal.pbio.1001874
186
RinaldiB. Bayat A ZachariassenL. G.SunJ. H.GeY. H.ZhaoD.et al. (2024). Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes. Brain147, 1837–1855. doi: 10.1093/brain/awad403
187
RinaldiB.GeY. H.FreriE.TucciA.GranataT. M.EstienneM.et al. (2022). Myoclonic status epilepticus and cerebellar hypoplasia associated with a novel variant in the GRIA3 gene. Neurogenetics23, 27–35.
188
RodriguesP. F.TussiwandR. (2020). Novel concepts in plasmacytoid dendritic cell (pDC) development and differentiation. Molec. Immunol. 126, 25–30. doi: 10.1016/j.molimm.2020.07.006
189
RogersS. W.AndrewsP. I.GahringL. C.WhisenandT.CauleyK.CrainB.et al. (1994). Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science265, 648–651. doi: 10.1126/science.8036512
190
Ron-HarelN.SchwartzM. (2009). Immune senescence and brain aging: can rejuvenation of immunity reverse memory loss?Trends Neurosci. 32, 367–375. doi: 10.1016/j.tins.2009.03.003
191
RowlandS. L.RiggsJ. M.GilfillanS.BugattiM.VermiW.KolbeckR.et al. (2014). Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model. J. Exp. Med. 211, 1977–1991. doi: 10.1084/jem.20132620
192
RulandC.RenkenH.KuzmanovI.MehrA. F. M.SchwarteK. M. Cerina M. et al. (2017). Chemokine CCL17 is expressed by dendritic cells in the CNS during experimental autoimmune encephalomyelitis and promotes pathogenesis of disease. Brain Behav. Immun. 66, 382–393. doi: 10.1016/j.bbi.2017.06.010
193
RussoE.GittoR.CitraroR.ChimirriA.De SarroG. (2012). New AMPA antagonists in epilepsy. Expert Opin. Investig. Drugs21, 1371–1389. doi: 10.1517/13543784.2012.705277
194
Sanchez-MelgarA.AlbasanzJ. L.Grinan-FerreC.PallasM.MartinM. (2020). Adenosine and metabotropic glutamate receptors are present in blood serum and exosomes from SAMP8 Mice: modulation by aging and resveratrol. Cells9:1628. doi: 10.3390/cells9071628
195
Santana-CoelhoD.dos BessaR. D.Romcy-PereiraR. N.de la FlorM. A.O'ConnorJ. C. (2026). The role of the kynurenine pathway in the pathophysiology of autism-like phenotype induced by maternal inflammation in male mice. Neurobiol. Disease220:107282. doi: 10.1016/j.nbd.2026.107282
196
ScheggiaD.StanicJ.ItaliaM.La GrecaF.ZianniE.BenussiA.et al. (2021). GluA3 autoantibodies induce alterations in dendritic spine and behavior in mice. Brain Behav. Immun. 97, 89–101. doi: 10.1016/j.bbi.2021.07.001
197
SchmidS.GuthmannA.RuppersbergJ. P.HerbertH. (2001). Expression of AMPA receptor subunit flip/flop splice variants in the rat auditory brainstem and inferior colliculus. J. Comp. Neurol.430, 160–171. doi: 10.1002/1096-9861(20010205)430:2<160::aid-cne1022>3.0.co;2-3
198
SekiguchiM.NishikawaK.AokiS.WadaK. (2002). A desensitization-selective potentiator of AMPA-type glutamate receptors. Brit. J. Pharmacol.136, 1033–1041. doi: 10.1038/sj.bjp.0704804
199
SerafiniB.RosicarelliB.MagliozziR.StiglianoE.CapelloE.MancardiG. L.et al. (2006). Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells. J. Neuropathol. Exp. Neurol. 65, 124–141. doi: 10.1093/jnen/65.2.124
200
ShaoH.ChungJ.LeeK.BalajL.MinC.CarterB. S.et al. (2015). Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nat. Commun. 6:6999. doi: 10.1038/ncomms7999
201
ShepherdJ. D.HuganirR. L. (2007). The cell biology of synaptic plasticity: AMPA receptor trafficking. Ann. Rev. Cell Develop. Biol.23, 613–643. doi: 10.1146/annurev.cellbio.23.090506.123516
202
SieC.PerezL. G.KreutzfeldtM.PotthastM.OhnmachtC.MerklerD.et al. (2019). Dendritic cell accumulation in the gut and central nervous system is differentially dependent on α4 Integrins. J. Immunol.203, 1417–1427. doi: 10.4049/jimmunol.1900468
203
SimonsM.RaposoG. (2009). Exosomes - vesicular carriers for intercellular communication. Curr. Opin. Cell Biol.21, 575–581. doi: 10.1016/j.ceb.2009.03.007
204
SinghT.PoterbaT.CurtisD.AkilH.Al EissaM.BarchasJ. F.et al. (2022). Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature604, 509–516. doi: 10.1038/s41586-022-04556-w
205
SolekC. M.FarooqiN.VerlyM.LimT. K.RuthazerE. S. (2018). Maternal immune activation in neurodevelopmental disorders. Dev. Dyn. 247, 588–619. doi: 10.1002/dvdy.24612
206
SoucyS. M.HuangJ. L.GogartenJ. P. (2015). Horizontal gene transfer: building the web of life. Nat. Rev. Genetics16, 472–482. doi: 10.1038/nrg3962
207
SoumelisV.LiuY. J. (2006). From plasmacytoid to dendritic cell: morphological and functional switches during plasmacytoid pre-dendritic cell differentiation. Eur. J. Immunol.36, 2286–2292. doi: 10.1002/eji.200636026
208
StanA. D.GhoseS.ZhaoC.HulseyK.MihalakosP.YanagiM.et al. (2015). Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia. Molec. Psychiat.20, 433–439. doi: 10.1038/mp.2014.54
209
StewartC. M.TsuiD. W. Y. (2018). Circulating cell-free DNA for non-invasive cancer management. Cancer Genet. 228/229, 169–179. doi: 10.1016/j.cancergen.2018.02.005
210
StineC. D.LuW. X.WolfM. E. (2001). Expression of AMPA receptor flip and flop mRNAs in the nucleus accumbens and prefrontal cortex after neonatal ventral hippocampal lesions. Neuropsychopharmacology24, 253–266. doi: 10.1016/S0893-133X(00)00212-8
211
StoneT. W. (1993). The neuropharmacology of quinolinic acid and kynurenic acids. Pharmacol. Revs.45, 309–379. doi: 10.1016/S0031-6997(25)00441-7
212
StoneT. W.ClanchyF. I. L.HuangY-. S.ChiangN. Y.DarlingtonL. G.WilliamsR. O. (2022). An integrated cytokine and kynurenine network as the basis of neuroimmune communication. Front. Neurosci. 16:1002004. doi: 10.3389/fnins.2022.1002004
213
StoneT. W.StoyN.DarlingtonL. G. (2013). An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol. Sci.34, 136–143. doi: 10.1016/j.tips.2012.09.006
214
StoneT. W.WilliamsR. O. (2023). Modulation of T cells by tryptophan metabolites in the kynurenine pathway. Trends Pharmacol. Sci. 44, 442–456. doi: 10.1016/j.tips.2023.04.006
215
StoneT. W.WilliamsR. O. (2024). Tryptophan metabolism as a ‘reflex' feature of neuroimmune communication: sensor and effector functions for the indoleamine-2, 3-dioxygenase kynurenine pathway. J. Neurochem.168, 3333–3357. doi: 10.1111/jnc.16015
216
StoneT. W.DarlingtonL. G. (2013). The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Brit. J. Pharmacol. 169, 1211–1227. doi: 10.1111/bph.12230
217
StoneT. W.ForrestC. M.DarlingtonL. G. (2012). Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection. FEBS J.279, 1386–1397. doi: 10.1111/j.1742-4658.2012.08487.x
218
SudoM.OkadoH.IinoM.TsuzukiK.MiwaA.KanegaeY.et al. (1999). Postsynaptic expression of Ca2+-permeable AMPA-type glutamate receptor channels by viral-mediated gene transfer. Molec. Brain Res.65, 176–185. doi: 10.1016/S0169-328X(98)00348-9
219
SudoM.TsuzukiK.OkadoH.MiwaA.OzawaS. (1997). Adenovirus-mediated expression of AMPA-type glutamate receptor channels in PC12 cells. Molec. Brain Res. 50, 91–99. doi: 10.1016/S0169-328X(97)00167-8
220
SukumaranM.RossmannM.ShrivastavaI.DuttaA.BaharI.GregerI. H. (2011). Dynamics and allosteric potential of the AMPA receptor N-terminal domain. EMBO J.30, 972–982. doi: 10.1038/emboj.2011.17
221
SunJ. H.ChenJ.ValenzuelaF. E. A.BrownC.Masser-FryeD.et al. (2021). X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3. PLoS Genet.17:e1009608. doi: 10.1371/journal.pgen.1009608
222
SunK.JiangP. Y.ChanK. C. A.WongJ.ChengY. K. Y.LiangR. H. S.et al. (2015). Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc. Natl. Acad. Sci. U.S.A.112, E5503–E5512. doi: 10.1073/pnas.1508736112
223
SunX.MilovanovicM. Y.WolfM. E. (2008). Acute and chronic dopamine receptor stimulation modulates AMPA receptor trafficking in nucleus Accumbens neurons cocultured with prefrontal cortex neurons. J. Neurosci.28, 4216–4230. doi: 10.1523/JNEUROSCI.0258-08.2008
224
SwieckiM.ColonnaM. (2010). Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev.234, 142–162. doi: 10.1111/j.0105-2896.2009.00881.x
225
SzymanskaE.ChalupnikP.JohansenT. N.NielsenB.MoralA. M. C.PickeringD. S.et al. (2017b). Aryl- and heteroaryl-substituted phenylalanines as AMPA receptor ligands. Chem. Biol. Drug Design90, 1271–1281. doi: 10.1111/cbdd.13048
226
SzymanskaE.NielsenB.JohansenT.MoralA. M. C.PickeringD. S.SzczepanskaK.et al. (2017a). Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors. Europ. J. Med. Chem. 138, 874–883. doi: 10.1016/j.ejmech.2017.07.007
227
TakagiH.FukayaT. Eizumi K. (2011). Plasmacytoid dendritic cells are crucial for the initiation of inflammation and T cell immunity in vivo. Immunity35, 958–971. doi: 10.1016/j.immuni.2011.10.014
228
TamkovichS. N.CherepanovaA. V.KolesnikovaE. V.RykovaE. Y.PyshnyiD. V.VlassovV. V.et al. (2006). Circulating DNA and DNase activity in human blood. Ann. N. Y. Acad. Sci. 1075, 191–196. doi: 10.1196/annals.1368.026
229
TammingaC. A.SouthcottS.SaccoC.WagnerA. D. Ghose S. (2012). Glutamate Dysfunction in hippocampus: relevance of dentate gyrus and CA3 signaling. Schizophr. Bull. 38, 927–935. doi: 10.1093/schbul/sbs062
230
TanakaM.SpekkerE.SzabóA.PolyákH.VécseiL. (2022). Modelling the neuro-developmental pathogenesis in neuropsychiatric disorders. Bioactive kynurenines and their analogues as neuroprotective agents. J. Neural Trans.129, 627–642. doi: 10.1007/s00702-022-02513-5
231
TheryC.OstrowskiM. Segura E. (2009). Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 9, 581–593. doi: 10.1038/nri2567
232
ThierryA. R.El MessaoudiS.GahanP. B.AnkerP.StrounM. (2016). Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev.35, 347–376. doi: 10.1007/s10555-016-9629-x
233
TiolecoN.SilbermanA. E.StratigosK.Banerjee-BasuS.SpannM. N.WhitakerA. H.et al. (2021). Prenatal maternal infection and risk for autism in offspring: a meta-analysis. Autism Res.14, 1296–1316. doi: 10.1002/aur.2499
234
TondreauT.DejeneffeM.MeulemanN.StamatopoulosB.DelforgeA. P.et al. (2008). Gene expression pattern of functional neuronal cells derived from human bone marrow mesenchymal stromal cells. BMC Genomics9:166. doi: 10.1186/1471-2164-9-166
235
TorresD. N.LeeS. H. (2023). Inter-neuronal signaling mediated by small extracellular vesicles: wireless communication?Front. Molec. Neurosci. 16:1187300. doi: 10.3389/fnmol.2023.1187300
236
ToyodaS.KikuchiM.AbeY.TashiroK.HandaT.KatayamaS.et al. (2025). Schizophrenia-related Xpo7 haploinsufficiency leads to behavioral and nuclear transport pathologies. EMBO Rep.26, 948–981. doi: 10.1038/s44319-024-00362-9
237
ToyodaH.WuL. J.ZhaoM. G.XuH.ZhuoM. (2007). Time-dependent postsynaptic AMPA GluR1 receptor recruitment in the cingulate synaptic potentiation. Develop. Neurobiol.67, 498–509. doi: 10.1002/dneu.20380
238
TraynelisS. F.WollmuthL. P.McBainC. J.MennitiF. S.VanceK. M.OgdenK. K.et al. (2010). Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496. doi: 10.1124/pr.109.002451
239
ValadiH.EkstromK.BossiosA.SjostrandM.LeeJ. J.LotvallJ. O.et al. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biol. 9, 654–U72. doi: 10.1038/ncb1596
240
ValczG.UjvariB.BuzasE. I. I.KrenacsT.SpisakS.KittelA.et al. (2022). Small extracellular vesicle DNA-mediated horizontal gene transfer as a driving force for tumor evolution: facts and riddles. Front. Oncol. 12:945376. doi: 10.3389/fonc.2022.945376
241
van der SpekS. J. F.PandyaN. J.KoopmansF. I.van der SchorsR. C.OttenM.et al. (2022). Expression and interaction proteomics of Glua1-and GluA3-subunit-containing AMPARs reveal distinct protein composition. Cells11:3648. doi: 10.3390/cells11223648
242
VarneyM. A.RaoS. P.JachecC.DealC.HessS. D.DaggettL. P.et al. (1998). Pharmacological characterization of the human ionotropic glutamate receptor subtype GluR3 stably expressed in mammalian cells. J. Pharmacol. Exp. Therap.285, 358–370. doi: 10.1016/S0022-3565(24)37383-5
243
VilladangosJ. A.YoungL. (2008). Antigen-presentation properties of plasmacytoid dendritic cells. Immunity29, 352–361. doi: 10.1016/j.immuni.2008.09.002
244
VolkC.JaramilloV.MerkiR.TuuraR. O.HuberR. (2018). Diurnal changes in glutamate plus glutamine levels of healthy young adults assessed by proton magnetic resonance spectroscopy. Hum. Brain Mapp. 39, 3984–3992. doi: 10.1002/hbm.24225
245
WaclecheV. S.TremblayC. L.RoutyJ. P.AncutaP. (2018). The biology of monocytes and dendritic cells: contribution to HIV pathogenesis. Viruses10:65. doi: 10.3390/v10020065
246
WangH. L.ZhangZ.HintzeM.ChenL. (2011). Decrease in calcium concentration triggers neuronal retinoic acid synthesis during homeostatic synaptic plasticity. J. Neurosci. 31, 17764–17771. doi: 10.1523/JNEUROSCI.3964-11.2011
247
WangS. Y.LarsenY. C.V.JensenA.A.NielsenB.Al-MusaedA. (2016) Tweaking Subtype Selectivity Agonist Efficacy at (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) Receptors in a Small Series of BnTetAMPA Analogues. J. Med. Chem.59, 2244–2254. 10.1021/acs.jmedchem.5b01982.
248
WentholdR. J.PetraliaR. S.BlahosJ. Niedzielski A. S. (1996). Evidence for multiple AMPA receptor complexes in hippocampal CA1/ CA2 neurons. J. Neurosci.16, 1982–1989. doi: 10.1523/JNEUROSCI.16-06-01982.1996
249
WuY.AraiA. C.RumbaughG.SrivastavaA. K.TurnerG.HayashiT.et al. (2007). Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans. Proc. Natl. Acad. Sci. U.S.A.104, 18163–18168. doi: 10.1073/pnas.0708699104
250
XiangWeiW. S.PerszykR. E.LiuN. N.XuYC.BhattacharyaS.ShaulskyG. H.et al. (2023). Clinical and functional consequences of GRIA variants in patients with neurological diseases. Cell. Molec. Life Sci. 80:345. doi: 10.1007/s00018-023-04991-6
251
YangS.CheS. P.KurywchakP.TavorminaJ. L.GansmoL. B.Correa de SampaioP.et al. (2017). Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer. Cancer Biol. Ther. 18, 158–165. doi: 10.1080/15384047.2017.1281499
252
YaoW.MeiC.NanX.HuiL. (2016). Evaluation and comparison of in vitro degradation kinetics of DNA in serum, urine and saliva: a qualitative study. Gene590, 142–148. doi: 10.1016/j.gene.2016.06.033
253
YatesE. F.MulkeyS. B. (2024). Viral infections in pregnancy and impact on offspring neurodevelopment: mechanisms and lessons learned. Pediatr. Res.96, 64–72. doi: 10.1038/s41390-024-03145-z
254
YeriA.CourtrightA.ReimanR.CarlsonE.BeecroftT.JanssA.et al. (2017). Total extracellular small RNA profiles from plasma, saliva, and urine of healthy subjects. Sci. Rep. 7:44061. doi: 10.1038/srep44061
255
YogevN.FrommerF.LukasD.Kautz-NeuK.KarramK.IeloD.et al. (2012). Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity37, 264–275. doi: 10.1016/j.immuni.2012.05.025
256
YuS.CaoH. B. Feng J. (2015). Tumor-derived exosomes in cancer progression and treatment failure. Oncotarget6, 37151–37168. doi: 10.18632/oncotarget.6022
257
YuanC. L.ShiE. Y.SrinivasanJ. C. P.OswaldR. E.NowakL. M. (2019). Modulation of AMPA receptor gating by the anticonvulsant drug, Perampanel. ACS Med. Chem. Lett. 10, 237–242. doi: 10.1021/acsmedchemlett.8b00322
258
ZachariassenL. G.KatchanL.JensenA. G.PickeringD. S.PlestedA. J. R.KristensenA. S. (2016). Structural rearrangement of the intracellular domains during AMPA receptor activation. Proc. Nat. Acad. Sci. U.S.A.113, E3950–E3959. doi: 10.1073/pnas.1601747113
259
ZappulliV.FriisK. P.FitzpatrickZ.MaguireC. A.BreakefieldX. O. (2016). Extracellular vesicles and intercellular communication within the nervous system. J. Clin. Invest. 126, 1198–1207. doi: 10.1172/JCI81134
260
ZhangT.DolgaA. M.EiselU. L. M.SchmidtM. (2024). Novel crosstalk mechanisms between GluA3 and Epac2 in synaptic plasticity and memory in Alzheimer's disease. Neurobiol. Dis. 191:106389. doi: 10.1016/j.nbd.2023.106389
261
ZhangT.MushesheN.van der VeenC. H. J. T. M.KesselsH. W.DolgaA.De DeynP. (2023) The expression of Epac2 GluA3 in an Alzheimer's disease experimental model postmortem patient samples. Biomedicines11:2096. 10.3390/biomedicines11082096.
262
ZhaoS.ZhangL.XiangS.HuY.WuZ.ShenJ. (2022). Gnawing between cells and cells in the immune system: friend or foe? A review of trogocytosis. Front. Immunol. 13:791006. doi: 10.3389/fimmu.2022.791006
263
ZhaoY.ChenS. S.YoshiokaC.BaconguisI.GouauxE. (2016). Architecture of fully occupied GluA2 AMPA receptor-TARP complex elucidated by cryo-EM. Nature536, 108–110. doi: 10.1038/nature18961
264
ZhouH.YanZ. H.YuanY.XingC.JiangN. (2021). The role of exosomes in viral hepatitis and its associated liver diseases. Front. Med. 8:782485. doi: 10.3389/fmed.2021.782485
265
ZhouY.XiaoZ.ZhuW. (2022). The roles of small extracellular vesicles as prognostic biomarkers and treatment approaches in triple-negative breast cancer. Front. Oncol. 12:998964. doi: 10.3389/fonc.2022.998964
266
ZouikrI.Hasegawa-IshiiS.ShimadaA. (2017). Neuroimmune interface in health and disease. Front. Immunol. 8:AR.0315. doi: 10.3389/fimmu.2017.01315
267
ZozulyaA. L.ClarksonB. D.OrtlerS.FabryZ.WiendlH. (2010). The role of dendritic cells in CNS autoimmunity. J. Mol. Med.88, 535–544. doi: 10.1007/s00109-010-0607-4
Summary
Keywords
AMPA receptors, chronic disorders, epilepsy, GRIA3: the gene producing protein GluA3, kynurenic acid, neuroimmune interface, plasmacytoid dendritic cells, schizophrenia
Citation
Stone TW, Clanchy FIL and Williams RO (2026) GRIA3: proposal for a neuroimmune role linking infection, stress, chronic disorders and the activity of kynurenic acid. Front. Cell. Neurosci. 20:1885761. doi: 10.3389/fncel.2026.1885761
Received
19 May 2026
Revised
10 July 2026
Accepted
20 July 2026
Published
10 August 2026
Volume
20 - 2026
Edited by
Laurent Seugnet, INSERM U1028 Centre de Recherche en Neurosciences de Lyon, France
Updates
Copyright
© 2026 Stone, Clanchy and Williams.
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*Correspondence: Trevor W. Stone, Trevor.Stone@kennedy.ox.ac.uk
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