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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 , 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 mice. We additionally discovered widespread splicing abnormalities and impaired hippocampal neurogenesis in mutants. Interestingly, the underlying genes and the spatial and temporal patterns of transcriptomic changes in mice differed substantially from those observed in mutant mice lacking , encoding the GluN2A subunit of NMDA receptors and a schizophrenia risk gene. These findings underscore the distinct role of in brain development and function and reveal potential mechanisms by which a lack of may lead to neurodevelopmental disorders.