SrcapHaploinsufficiency Induced Autistic-Like Behaviors in Mice through Disruption ofSatb2Expression

Abstract

AbstractAutism spectrum disorder (ASD) is a complex neurodevelopmental disorder with significant genetic predispositions. Among these, loss-of-function mutations of the chromatin remodeling geneSRCAPhave been identified in individuals with ASD, but their pathogenic mechanisms have yet to be fully elucidated. In this study, we established a germline mutant mouse model harboring a heterozygous frameshift mutation in theSrcapgene (Srcap+/-). TheSrcap+/-mice exhibited notable impairments in social novelty, repetitive and stereotyped behaviors, anxiety, and learning and memory deficits. We observed a decreased number of parvalbumin (PV)-expressing neurons in their retrosplenial cortex (RSC) and dentate gyrus (DG). Furthermore, abnormalities in dendritic structure, synaptic density, and synaptic transmission were noted in the DG ofSrcap+/-mice. RNA sequencing revealed that the expression of 27 genes, implicated in ASD, was dysregulated in theSrcaphaploinsufficiency mice. Among these genes, we found thatSrcaphaploinsufficiency resulted in decreasedSatb2expression due to diminished H2A.z-binding within the promoter region ofSatb2. Remarkably, intervention through retro-orbital injection of AAV vectors expressingSatb2in newbornSrcap+/-mice reversed autistic-like behaviors and developmental defects in the RSC and DG regions. Similarly, in adolescentSrcap+/-mice, stereotactic injection of AAV expressingSatb2into the RSC ameliorated deficits in social novelty. Collectively, these findings highlight the crucial role of theSrcapin neurodevelopment by regulatingSatb2expression, particularly impacting the development of RSC and DG regions.