Cognitive and synaptic impairment induced by deficiency of autism risk gene Smarcc2 and its rescue by histone deacetylase inhibition

SMARCC2, which encodes BAF170, a core subunit of chromatin remodeling BAF complex, is one of the top-ranking risk genes for autism spectrum disorder (ASD). However, the mechanisms linking SMARCC2 haploinsufficiency to ASD remain poorly understood. ChIP-seq of SMARCC2 demonstrated its binding to many other ASD risk genes involved in transcriptional regulation. SMARCC2 expression was significantly reduced in the nuclear fraction of postmortem prefrontal cortex (PFC) from patients with ASD. Smarcc2 deficiency in PFC of adolescent mice led to impaired working memory, with largely intact social and anxiety-like behaviors. Significant downregulation of genes enriched in synaptic transmission was found in PFC of Smarcc2-deficient mice by RNA-seq and qPCR profiling. Furthermore, SMARCC2 was reduced in human iPSC-derived neurons (hiPSC-N) from ASD patients, and synaptic genes were downregulated by SMARCC2 knockdown in hiPSC-N. In parallel, electrophysiological recordings uncovered the significant impairment of GABAergic and glutamatergic synaptic currents in PFC pyramidal neurons of Smarcc2-deficient mice. Smarcc2 bound to HDAC2, and Smarcc2 deficiency led to the reduced global histone acetylation and H3K9ac enrichment at synaptic gene promoters. Treatment of Smarcc2-deficient mice with romidepsin, a class I HDAC inhibitor, normalized histone acetylation, working memory, synaptic genes and currents. These findings highlight the critical role of Smarcc2 in regulating cognitive and synaptic function, suggesting that targeting HDAC could alleviate deficits in Smarcc2-associated neurodevelopmental disorders.