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CYFIP1 dosages exhibit divergent behavioral impact via diametric regulation of NMDAR complex translation in mouse models of psychiatric disorders

ABSTRACT: Gene dosage imbalance caused by copy number variations (CNVs) are prominent contributors to brain disorders. 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), respectively. The mechanism underlying these diametric contributions remain unclear. Here we established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs and these mice exhibited both distinct and shared behavioral abnormalities related to ASD and SCZ. RIP-seq analysis identified mRNA targets of CYFIP1 in vivo, including postsynaptic NMDAR complex components. These mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses due to dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in mouse models with diametric CYFIP1 dosages rescues behavioral abnormalities. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE166939 | GEO | 2022/02/02

REPOSITORIES: GEO

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