Roles of the nuclear receptor corepressor 1 (NCoR1) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT) in the developing brain

The nuclear receptor corepressor 1 (NCoR1) and the silencing mediator of retinoic acid and thyroid hormone (SMRT) are critical coregulators of nuclear receptors, including the thyroid hormone receptor and they mediate transcriptional repression via histone deacetylation. Although they are highly homologous and have similar receptor interacting domains, they have different roles in different tissues. Recently, de novo genetic variants in nuclear corepressors were found in pediatric patients with neurodevelopmental disorders. Thus, we generated novel mouse models to understand the role of NCOR1 and SMRT in the central nervous system. We used the mice with conditional NCoR1 or SMRT (NCoR1lox/lox or SMRTlox/lox) alleles in combination with the mice that express Cre recombinase in a neuronal specific fashion (Snap25-IRES2-cre). First, we performed behavioral tests to assess for any behavioral phenotypes. We found hypoactivity, social deficits, and mild anxiety in neuronal specific deletion of NCoR1 or SMRT KO mice. In addition, NCoR1 KO mice displayed higher learning abilities in a pairwise visual discrimination task. Next, we performed RNA-sequencing analysis with cells from the amygdala taken at postnatal day 21 to investigate gene expression mediated by NCoR1 and SMRT. We found that 449 genes were upregulated by SMRT deletion, whereas only 8 genes were upregulated by NCoR1 deletion. Overall, our data demonstrate that NCoR1 and SMRT have separate functions in the central nervous system.