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Here we report that \u03b17nAChRs on principal and inhibitory forebrain neurons are largely inconsequential to mouse behavior, including in domains that are most sensitive to schizophrenia-related cognitive impairments. By contrast, loss of \u03b17nAChR from astrocytes produces profound behavioral alterations that are cognitive domain-specific, are time-of-day dependent, coincide with reduced levels of the N-methyl D-aspartate receptor (NMDAR) co-agonist D-serine, and are fully restored by D-serine supplementation. Further, an \u03b17nAChR partial agonist previously evaluated in Phase III trials for cognitive enhancement in schizophrenia and AD fails to augment behavior in mice lacking astrocytic \u03b17nAChRs. Together, these findings identify astrocytes and D-serine\/NMDAR signaling as a central mechanism through which \u03b17nAChR, a major drug target, promotes cognitive behavior.<\/jats:p>","DOI":"10.64898\/2026.04.16.719027","type":"posted-content","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T10:30:16Z","timestamp":1776594616000},"source":"Crossref","is-referenced-by-count":1,"title":["Astrocytes mediate the pro-cognitive value of \u03b17nAChRs and of \u03b17nAChR-targeting therapeutics"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0028-8457","authenticated-orcid":false,"given":"Yifan","family":"Wu","sequence":"first","affiliation":[{"name":"Washington University in St Louis, School of Medicine, Department of Neuroscience, St Louis, MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Tolman","sequence":"additional","affiliation":[{"name":"Tufts University School of Medicine, Neuroscience Department, Boston, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6169-514X","authenticated-orcid":false,"given":"Yanchao","family":"Dai","sequence":"additional","affiliation":[{"name":"Washington University in St Louis, School of Medicine, Department of Neuroscience, St Louis, MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Walsh","sequence":"additional","affiliation":[{"name":"Washington University in St Louis, School of Medicine, Department of Neuroscience, St Louis, MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humza","family":"Agha","sequence":"additional","affiliation":[{"name":"Washington University in St Louis, School of Medicine, Department of Neuroscience, St Louis, MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katheryn B.","family":"Lefton","sequence":"additional","affiliation":[{"name":"Washington University in St Louis, School of Medicine, Department of Neuroscience, St Louis, MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"An","sequence":"additional","affiliation":[{"name":"Washington University in St Louis, School of Medicine, Department of Neuroscience, St Louis, MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Manno","sequence":"additional","affiliation":[{"name":"Washington University in St Louis, School of Medicine, Department of Neuroscience, St Louis, MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip G.","family":"Haydon","sequence":"additional","affiliation":[{"name":"Tufts University School of Medicine, Neuroscience Department, Boston, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5288-1944","authenticated-orcid":false,"given":"Thomas","family":"Papouin","sequence":"additional","affiliation":[{"name":"Washington University in St Louis, School of Medicine, Department of Neuroscience, St Louis, MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026042109451098000_2026.04.16.719027v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-01949-9"},{"key":"2026042109451098000_2026.04.16.719027v1.2","doi-asserted-by":"publisher","DOI":"10.31887\/DCNS.2006.8.1\/smarder"},{"key":"2026042109451098000_2026.04.16.719027v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3223(94)00252-X"},{"key":"2026042109451098000_2026.04.16.719027v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-0618(01)00117-X"},{"key":"2026042109451098000_2026.04.16.719027v1.5","doi-asserted-by":"crossref","unstructured":"Leonard, S. et al. 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