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

Nuclear receptor corepressor 1 (NCoR1) and silencing mediator of retinoic acid and thyroid hormone (SMRT) are critical regulators that mediate transcriptional repression through histone deacetylation. Despite high structural homology, their distinct roles in the central nervous system remain poorly understood. To elucidate these roles, we generated neuronal-specific NCoR1 or SMRT knockout mice using Snap25-IRES2-Cre mice. Behavioral assessments revealed that while both NCoR1 and SMRT deficiency led to hypoactivity, social deficits, and mild anxiety, NCoR1-deficient mice uniquely exhibited enhanced learning abilities in a visual discrimination task, indicating functional separation in cognitive regulation. This divergence was supported by RNA-sequencing in the amygdala at postnatal day 21 (PND 21), where SMRT deletion upregulated 449 genes, whereas NCoR1 deletion upregulated only 8 genes. Furthermore, we investigated the protein stability of HDAC3, the primary enzymatic partner of these corepressors. At PND 21, HDAC3 levels were significantly reduced in the NCoR1-deficient hippocampus but significantly increased in the SMRT-deficient amygdala. In contrast, HDAC3 levels remained stable in the adult cerebellum and PND 3 cerebrum regardless of corepressor status. Notably, while mice with deletion of both NCoR1 and SMRT exhibit early postnatal lethality, their HDAC3 levels were unchanged compared to controls at PND 3, suggesting that the lethal phenotype is not primarily driven by a systemic loss of HDAC3 protein. Collectively, our findings demonstrate that NCoR1 and SMRT function through independent transcriptional networks and context-dependent regulatory mechanisms. This study highlights the specialized, non-redundant roles of these homologous corepressors in the brain according to developmental stage and region.