Drug Repurposing for Treating NCOR‐Related Intellectual Disability

ABSTRACT Nuclear receptor corepressors (NCOR1/2) mediate the transcriptional activity of methyl‐CpG binding protein 2 (MECP2), and genetic variants in NCOR1/2 or MECP2 associate with autism or intellectual disability. However, it is unknown whether heterozygous NCOR mutations impair cognitive functions and how NCOR‐related intellectual disability can be treated. Here, we constructed a knock‐in (KI) mouse line carrying a heterozygous NCOR1 mutation ( NCOR1 c.2182+2T>G) found in a pediatric patient. These NCOR1 KI/+ mice showed social avoidance, stereotypic behaviors, and memory deficits, similar to heterozygous NCOR1 knockout mice, demonstrating NCOR1 haploinsufficiency. snRNA‐seq revealed upregulated neuregulins ( Nrg1/3 ) and downregulated γ‐aminobutyric acid (GABA) receptor subunit ( Gabra2 ) in hypothalamic GABAergic neurons in NCOR1 KI/+ mice. In cultured neurons, Nrg1 overexpression is sufficient to downregulate Gabra2 . Spironolactone, an NRG antagonist, prevents Gabra2 downregulation induced by full‐length NRG1, but not by the NRG1 intracellular domain, suggesting that the noncanonical NRG backward signaling contributes to Gabra2 downregulation upon NCOR1 loss‐of‐function. Spironolactone and the GABA‐A receptor positive modulator allopregnanolone, both FDA‐approved drugs, mitigated cognitive impairments in NCOR1 KI/+ mice. Furthermore, spironolactone improved learning in an autistic patient bearing a pathogenic mutation in MECP2 . These findings elucidate the mechanism of NCOR‐related cognitive dysfunctions and provide preclinical proof‐of‐concept for treatment through drug repurposing.