Aberrant mRNA splicing and impaired hippocampal neurogenesis in <i>Grin2b</i> mutant mice

NMDA receptor dysfunction is implicated in the pathophysiology of autism spectrum disorder (ASD). Here, we investigated heterozygous mouse mutants carrying the ASD-linked C456Y mutation of <i>Grin2b</i>, a high-confidence ASD risk gene encoding the GluN2B subunit of NMDA receptors. Comprehensive transcriptomic analyses across brain regions and postnatal ages revealed large-scale gene expression changes, particularly in pathways related to oxidative phosphorylation and ribosome/translation, suggesting brain-wide alteration of energy metabolism and protein synthesis in <i>Grin2b</i> ^{<i>+/C456Y</i>} mice. We additionally discovered widespread splicing abnormalities and impaired hippocampal neurogenesis in <i>Grin2b</i> mutants. Interestingly, the underlying genes and the spatial and temporal patterns of transcriptomic changes in <i>Grin2b</i> ^{<i>+/C456Y</i>} mice differed substantially from those observed in mutant mice lacking <i>Grin2a</i>, encoding the GluN2A subunit of NMDA receptors and a schizophrenia risk gene. These findings underscore the distinct role of <i>Grin2b</i> in brain development and function and reveal potential mechanisms by which a lack of <i>Grin2b</i> may lead to neurodevelopmental disorders.