GRIN2A (NR2A): a gene contributing to glutamatergic involvement in schizophrenia

Abstract

Involvement of the glutamate system, particularly N-methyl-D-aspartate (NMDA) receptor hypofunction, has long been postulated to be part of the pathophysiology of schizophrenia. An important development is provided by recent data that strongly implicate GRIN2A, the gene encoding the NR2A (GluN2A) NMDA receptor subunit, in the aetiology of the disorder. Rare variants and common variants are both robustly associated with genetic risk for schizophrenia. Some of the rare variants are point mutations likely affecting channel function, but most are predicted to cause protein truncation and thence result, like the common variants, in reduced gene expression. We review the genomic evidence, and the findings from Grin2a mutant mice and other models which give clues as to the likely phenotypic impacts of GRIN2A genetic variation. We suggest that one consequence of NR2A dysfunction is impairment in a form of hippocampal synaptic plasticity, producing deficits in short-term habituation and thence elevated and dysregulated levels of attention, a phenotype of relevance to schizophrenia and its cognitive aspects.

Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation

“…These findings provide an unprecedented opportunity to model and study molecular, cellular and circuit changes relevant to schizophrenia pathology. The finding of Grin2a loss of function mutations is consistent with the long existing glutamate hypofunction hypothesis of schizophrenia pathology 5,45,46 . Indeed, mice with Grin2a genetic mutations have been used as a model for schizophrenia based on this hypothesis long before the current genetic evidence.…”

“…Indeed, mice with Grin2a genetic mutations have been used as a model for schizophrenia based on this hypothesis long before the current genetic evidence. While in humans, the variations of the Grin2a gene were found in the form of point mutations in heterozygous patients, most of the behavioral phenotypes for loss of function in Grin2a were found in NR2A full knockout mice 45,46 . The robust cognitive phenotype in heterozygous Grin2a Y700X+/− mice provides an opportunity to dissect neurobiological mechanisms in a system more closely modeling the genetic risks of schizophrenia.…”

Pharmacologic and genetic evidence converge on mechanisms of psychotic illness

“…GRIN2A was associated with schizophrenia through rare LoF variants in the SCHEMA study, but the clinical presentations of the schizophrenia cases harboring these variants in that study were not described 26 . The results in the previous section suggest activation of GRIN2A is a promising mechanism to pursue in developing novel antipsychotics, and since schizophrenia is a heterogeneous clinical condition, it is possible that activation of GRIN2A may be most promising for treating individuals with a specific clinical presentation.…”

NMDA Receptors in Health and Disease

“…Several genes that encode NMDAR subunits or modulate their function have been associated with schizophrenia risk or altered expression in patients. For example, GRIN2A, which codes for the GluN2A subunit of the NMDAR, has been firmly linked to schizophrenia by genome-wide association studies (GWAS) and meta-analyses [79][80][81]. To a lesser extent of confidence, schizophrenia has also been linked to gene mutations in GRIN2B, GRIN2C, GRIN2D, GRIN3A, and GRIN3B [82][83][84].…”