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Adv."],"published-print":{"date-parts":[[2026,1,9]]},"abstract":"<jats:p>\n                    The GluN2B subunit of\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -methyl-\n                    <jats:sc>d<\/jats:sc>\n                    -aspartate receptors (NMDARs) plays a central role in synaptic development and plasticity, and its hypofunction is linked to autism spectrum disorder (ASD), severe neurodevelopmental delay, and other neuropsychiatric diseases. Therefore, enhancing the function of this NMDAR subunit may provide an effective therapeutic strategy for correcting synaptic and behavioral deficits associated with GluN2B hypofunction. Here, we developed a class of GluN2B-selective positive allosteric modulators and characterized the pharmacological properties and binding site of the lead compound, 175. Systemic application of 175 facilitates hippocampal long-term depression in rats. 175 restores performances in open-field exploration and three-chamber test in\n                    <jats:italic toggle=\"yes\">Mecp2<\/jats:italic>\n                    overexpression mice that exhibit GluN2B hypofunction and autism-like features. Treatment with 175 also reverses behavioral abnormalities in open-field, Y-maze spontaneous alternation, three-chamber test, and prepulse inhibition in\n                    <jats:italic toggle=\"yes\">Disc1<\/jats:italic>\n                    mutant mice. Our findings introduce a pharmacological tool for selectively potentiating GluN2B-NMDAR function and highlight its therapeutic potential for cognitive and behavioral symptoms associated with GluN2B hypofunction.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.ady3891","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T18:58:58Z","timestamp":1767985138000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["GluN2B-specific NMDAR positive allosteric modulation reverses cognitive and behavioral abnormalities in\n                    <i>Mecp2<\/i>\n                    and\n                    <i>Disc1<\/i>\n                    transgenic mice"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3139-9053","authenticated-orcid":true,"given":"Yang","family":"Ge","sequence":"first","affiliation":[{"name":"Djavad Mowafaghian Centre for Brain Health and 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Neuroscience Center, Fudan University, Shanghai, PR China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Qin","sequence":"additional","affiliation":[{"name":"Djavad Mowafaghian Centre for Brain Health and Department of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mudi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Djavad Mowafaghian Centre for Brain Health and Department of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7728-8268","authenticated-orcid":true,"given":"Qi-Cheng","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Finance, Southwestern University of Finance and Economics, Chengdu, PR 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