GRIN2A and Schizophrenia: Scientific Evidence and Biological Mechanisms

Fig. (1). Subunit composition of GluN1/2 NMDA receptors. (A) NMDARs are large heterotetrameric protein complexes comprised of different subunits that form a central cation-permeable channel pore, including two obligate GluN1 subunits encoded by GRIN1 and two GluN2 subunits (GluN2A-GluN2D) encoded by GRIN2A-GRIN2D. (B) The crystal structure of the GluN1 and GluN2 subunits (created with AlphaFold Monomer v2.0). (C) All NMDAR subunits share a similar architecture that consist of four domains: a highly homologous extracellular amino-terminal domain (ATD), a bilobed ligand-binding domain (LBD), a pore-forming transmembrane domain (TMD) comprised of three transmembrane regions and a re-entrant ion pore-lining loop, and an intracellular carboxyl-terminal domain (CTD). (D) The crystal structure of the GluN1/GluN2 NMDAR (Protein Data Bank accession no. 4PE5; [102]) shows the subunit arrangement and the layered domain organization. Agonist binding sites as well as known and predicted binding sites for positive and negative allosteric modulators (PAMs and NAMs) are highlighted. Panels (C) and (D) are adapted from Hansen et al. [103]. The figure was generated using BioRender (Agreement number:…

Fig. (2). Autoradiograms of in situ hybridization conducted with oligonucleotide probes on parasagittal sections of rat brains on designated postnatal (P) days (day 1, 3, 7, 11, 14, 21, and 56). The figure shows the distributions of mRNAs for the five NMDA receptor subunits: GluN1 (NR1), GluN2A (NR2A), GluN2B (NR2B), GluN2C (NR2C), and GluN2D (NR2D). GluN2A is predominantly expressed in the forebrain at birth and progressively increases throughout the CNS until adulthood. While the expression of GluN2B is widely distributed at an early stage and reaches its peak at approximately P7. By comparison, GluN2C expression is confined to the cerebellum and the olfactory bulb and starts in the second postnatal week [44]. GluN2D expression is found mostly in the mid-brain structures such as the diencephalon and mesencephalon, while it is significantly decreased in the adult. The figure is adapted from Akazawa et al. [44]. Scale bar = 10 mm.

Fig. (3). The schematic diagram for the functional consequences of GRIN2A variants involved in schizophrenia. GRIN2A variants, including common and rare variants, were proposed to lead to reduced GRIN2A expression and GluN2A-containing NMDARs, while the missense variants in GRIN2A would cause aberrant GluN2A function and thence impaired GluN2A-containing NMDARs. Finally, these function declines in GluN2A-containing NMDARs might reduce the synaptic transmission and plasticity, and consequently result in the onset of schizophrenia.

Fig. (4). The Schizophrenia Exome Sequencing Meta-Analysis Consortium (SCHEMA) has identified multiple rare loss-of-function genetic variants in one of the largest sequencing studies to date of 24,248 cases and 97,322 controls, such as GRIN2A mutations [30]. Herzog et al. found GRIN2a+/− and −/− mice exhibited gene dose-dependent increases in gamma oscillations and sleep spindles compared with WT [45]. Moreover, relative to WT, GRIN2a mutants showed attenuated auditory steady-state responses (ASSR) at gamma frequencies and reduced responses to deviant auditory stimuli in the Mismatch negativity (MMN) paradigm [45]. The EEG phenotypes of GRIN2a mutant mice showed a variety of abnormal features that overlapped considerably with human schizophrenia patients. The figure was generated using BioRender (Agreement number: KV27791A2V).

Fig. (5). Pregnant rats exposed to polyriboinosinic-polyribocytidylic acid (Poly I:C; 5 mg/kg) at gestation day (GD)15 showed schizophrenia-like behaviors and abnormal neurotransmissions (increased mRNA expression of the Grin2a subunit) in the prefrontal cortex (PFC) via elevated neuroinflammation responses (NF-κB-NLRP3-IL-1β inflammatory signaling) [63]. Abbreviations: NF-κB: nuclear factor kappaB; NLRP3: pyrin domain containing 3; qRT-PCR: quantitative real-time PCR. The figure was generated using BioRender (Agreement number: NX27791J5S).

Fig. (6). It was found that a lack of GluN2A delayed the maturation of PVIs and PNNs in GRIN2A KO mice, while PVIs and PNNs appeared normal in ACC of late adolescent/young adult GRIN2A KO mice [78]. Moreover, GRIN2A KO mice at early postnatal age (PD20) showed weakened antioxidant defenses and greater vulnerability to an early postnatal oxidative insult as compared to WT mice. Finally, an early postnatal oxidative insult had long-term effects on PVI and PNN integrity, microglia activation, and local fast oscillatory neuronal activity in GRIN2A KO mice at late adolescence/early adulthood (PD60) [78]. Abbreviations: PVIs: parvalbumin-expressing interneurons; PNNs: perineuronal nets; ACC: anterior cingulate cortex. The figure was generated using BioRender (Agreement number: HK27791QG9).