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.

The evaluation of arginine vasopressin resistance (AVP-R) and arginine vasopressin deficiency (AVP-D), respectively, previously referred to as nephrogenic and central diabetes insipidus, often includes brain magnetic resonance imaging (MRI). Its purpose is to assess pituitary structural changes and identify the physiological T1 hyperintensity of the posterior pituitary, present in most individuals. This hyperintensity reflects vasopressin storage, which shortens the T1 relaxation time. Its absence supports a diagnosis of AVP-D over AVP-R. A 13-year-old boy was referred to endocrinology in his second year of life for polyuria and polydipsia. Brain MRI revealed normal pituitary morphology and a spontaneous T1 hyperintensity of the posterior pituitary. The AVP-R was confirmed by a hemizygous AVPR2 gene mutation. Treatment with hydrochlorothiazide, potassium supplementation, and dietary sodium restriction achieved good clinical control. During school age, progressive growth deceleration led to short stature and delayed puberty. At 13 years, repeated MRI showed a smaller pituitary gland and loss of the posterior pituitary T1 hyperintensity. Loss of posterior pituitary T1 hyperintensity is rare in AVP-R, and late disappearance has not been previously described in genetically confirmed cases. This case underscores the importance of integrating clinical, genetic, and imaging findings.