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We examined the acute and long-lasting effects of psilocybin (1\u2009mg\/kg, intraperitoneal) on behavioral and neural outcomes in the metabotropic glutamate receptor 5 (mGlu5) knockout (KO) mouse model of schizophrenia. The mGlu5 KO mice displayed psilocybin-induced hyperlocomotion, whereas wild-type (WT) mice did not. Additionally, male mGlu5 KO mice showed an amplified psilocybin-induced head-twitch response (HTR) compared with WT males, consistent with sex-dependent enhancement of 5-HT\n                    <jats:sub>2A<\/jats:sub>\n                    receptor-mediated signaling. Acute psilocybin increased c-Fos expression in the claustrum of WT but not KO mice, suggesting intact mGlu5 signaling is required for psilocybin-evoked claustral recruitment. Psilocybin did not alter anxiety-like behavior in the light\u2013dark box and increased immobility time\u00a0in the Porsolt test. Strikingly, psilocybin produced a sustained normalization in prepulse inhibition (a measure of sensorimotor gating) in female KO mice, evident nine days after treatment. Together, these findings indicate that disrupted mGlu5 signaling amplifies acute responses to psilocybin and reveals a sex-dependent long-term effect on sensorimotor gating. These results refine understanding of glutamatergic\u2013serotonergic interactions and motivate further work evaluating psilocybin across schizophrenia-relevant endophenotypes.\n                  <\/jats:p>","DOI":"10.1038\/s41386-026-02501-3","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T05:52:03Z","timestamp":1784353923000},"page":"2111-2123","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Psilocybin produces amplified acute responses and sex-specific long-term increases in sensorimotor gating in the mGlu5 knockout mouse model of schizophrenia"],"prefix":"10.1038","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0543-8728","authenticated-orcid":false,"given":"James J.","family":"Gattuso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Kamal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennyfer M.","family":"Payet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kato","family":"Havaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Hendey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilgenur","family":"Bezcioglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe J.","family":"Phelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddy","family":"Orchard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divyesh","family":"Bhanot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Hale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7532-8922","authenticated-orcid":false,"given":"Anthony J.","family":"Hannan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thibault","family":"Renoir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"2501_CR1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.books.9780890425596","volume-title":"Diagnostic and statistical manual of mental disorders: DSM-5. vol. 5.","author":"DS American Psychiatric Association","year":"2013","unstructured":"American Psychiatric Association DS, Association AP Diagnostic and statistical manual of mental disorders: DSM-5. vol. 5. 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