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However, it is unknown whether heterozygous NCOR mutations impair cognitive functions and how NCOR\u2010related intellectual disability can be treated. Here, we constructed a knock\u2010in (KI) mouse line carrying a heterozygous\n                    <jats:italic>NCOR1<\/jats:italic>\n                    mutation (\n                    <jats:italic>NCOR1<\/jats:italic>\n                    c.2182+2T&gt;G) found in a pediatric patient. These NCOR1\n                    <jats:sup>KI\/+<\/jats:sup>\n                    mice showed social avoidance, stereotypic behaviors, and memory deficits, similar to heterozygous\n                    <jats:italic>NCOR1<\/jats:italic>\n                    knockout mice, demonstrating\n                    <jats:italic>NCOR1<\/jats:italic>\n                    haploinsufficiency. snRNA\u2010seq revealed upregulated neuregulins (\n                    <jats:italic>Nrg1\/3<\/jats:italic>\n                    ) and downregulated \u03b3\u2010aminobutyric acid (GABA) receptor subunit (\n                    <jats:italic>Gabra2<\/jats:italic>\n                    ) in hypothalamic GABAergic neurons in NCOR1\n                    <jats:sup>KI\/+<\/jats:sup>\n                    mice. In cultured neurons,\n                    <jats:italic>Nrg1<\/jats:italic>\n                    overexpression is sufficient to downregulate\n                    <jats:italic>Gabra2<\/jats:italic>\n                    . Spironolactone, an NRG antagonist, prevents\n                    <jats:italic>Gabra2<\/jats:italic>\n                    downregulation induced by full\u2010length NRG1, but not by the NRG1 intracellular domain, suggesting that the noncanonical NRG backward signaling contributes to\n                    <jats:italic>Gabra2<\/jats:italic>\n                    downregulation upon\n                    <jats:italic>NCOR1<\/jats:italic>\n                    loss\u2010of\u2010function. Spironolactone and the GABA\u2010A receptor positive modulator allopregnanolone, both FDA\u2010approved drugs, mitigated cognitive impairments in NCOR1\n                    <jats:sup>KI\/+<\/jats:sup>\n                    mice. Furthermore, spironolactone improved learning in an autistic patient bearing a pathogenic mutation in\n                    <jats:italic>MECP2<\/jats:italic>\n                    . These findings elucidate the mechanism of NCOR\u2010related cognitive dysfunctions and provide preclinical proof\u2010of\u2010concept for treatment through drug repurposing.\n                  <\/jats:p>","DOI":"10.1002\/advs.78030","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T04:16:42Z","timestamp":1791778602000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Drug Repurposing for Treating NCOR\u2010Related Intellectual Disability"],"prefix":"10.1002","author":[{"given":"Yan","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology School of Medicine Southeast University  Nanjing Jiangsu China"},{"name":"Department of Medicine \u2013 Division of Endocrinology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8268-0251","authenticated-orcid":false,"given":"Wenjun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medicine \u2013 Division of Endocrinology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0915-6557","authenticated-orcid":false,"given":"Yuxiang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medicine \u2013 Division of Endocrinology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology School of Medicine Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shandong University Qilu Hospital  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6639-3746","authenticated-orcid":false,"given":"Udhaya","family":"Kumar. 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Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Medicine \u2013 Division of Endocrinology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengchuang","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medicine \u2013 Division of Endocrinology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7828-4248","authenticated-orcid":false,"given":"Veronica C.","family":"Ciliberto","sequence":"additional","affiliation":[{"name":"Department of Medicine \u2013 Division of Endocrinology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makenna","family":"Mack","sequence":"additional","affiliation":[{"name":"Department of Medicine \u2013 Division of Endocrinology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4084-1277","authenticated-orcid":false,"given":"Lana E.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine \u2013 Division of Endocrinology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4171-3587","authenticated-orcid":false,"given":"Zhaoyong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Medicine \u2013 Division of Endocrinology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Luo","sequence":"additional","affiliation":[{"name":"MyGenostics Inc.  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