Aberrant mRNA Splicing and Impaired Hippocampal Neurogenesis in Grin2b Mutant Mice [RNAseq]

NMDA (N-methyl-d-aspartate) receptor dysfunction is widely implicated in pathophysiology of autism spectrum disorder (ASD), a neurodevelopmental condition with a strong genetic basis. Here we investigated heterozygous mouse mutants carrying the ASD-linked C456Y mutation of Grin2b, a high-confidence ASD risk gene encoding the GluN2B subunit of the NMDA receptors. Comprehensive transcriptomic analyses across multiple 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 Grin2b+/C456Y mice. Starting from transcriptomic evidence, we additionally discovered widespread splicing abnormalities, and impaired hippocampal neurogenesis in Grin2b mutants. Interestingly, the underlying genes and the spatial and temporal patterns of transcriptomic changes in Grin2b+/C456Y mice differed substantially from those observed in mutant mice lacking Grin2a, which encodes the GluN2A subunit of the NMDA receptor but is a schizophrenia risk gene. These findings underscore the distinct role of Grin2b in brain development and function and reveal potential mechanisms by which Grin2b loss of function may lead to neurodevelopmental disorders.