Drug Repurposing for Treating NCOR-Related Intellectual Disability.

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 NCOR1KI/+ 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 NCOR1KI/+ 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 NCOR1KI/+ 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.