{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:06:58Z","timestamp":1790622418163,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["DPA20140629800"],"award-info":[{"award-number":["DPA20140629800"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004794","name":"Centre National de la Recherche Scientifique","doi-asserted-by":"publisher","award":["Dotation"],"award-info":[{"award-number":["Dotation"]}],"id":[{"id":"10.13039\/501100004794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["Dotation"],"award-info":[{"award-number":["Dotation"]}],"id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008222","name":"Universit\u00e9 de Montpellier","doi-asserted-by":"publisher","award":["Dotation"],"award-info":[{"award-number":["Dotation"]}],"id":[{"id":"10.13039\/501100008222","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Neurofibromatosis Northeast","award":["Post-doctoral fellowship"],"award-info":[{"award-number":["Post-doctoral fellowship"]}]},{"DOI":"10.13039\/501100018874","name":"Laboratoire d'Excellence EpiGenMed","doi-asserted-by":"publisher","award":["Postdoctoral Fellowship"],"award-info":[{"award-number":["Postdoctoral Fellowship"]}],"id":[{"id":"10.13039\/501100018874","id-type":"DOI","asserted-by":"publisher"}]},{"name":"French Association Kokcinelo","award":["financial support"],"award-info":[{"award-number":["financial support"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT6 receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT6 receptors contribute to increased mTOR activity in the brain of Nf1+\/\u2212 mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT6 receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1+\/\u2212 mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT6 receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT6 receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients.<\/jats:p>","DOI":"10.3390\/ijms221810178","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T22:34:01Z","timestamp":1632263641000},"page":"10178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Blockade of Serotonin 5-HT6 Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1"],"prefix":"10.3390","volume":"22","author":[{"given":"Emilie","family":"Doucet","sequence":"first","affiliation":[{"name":"Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, 34094 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Grychowska","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6192-8721","authenticated-orcid":false,"given":"Pawel","family":"Zajdel","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00ebl","family":"Bockaert","sequence":"additional","affiliation":[{"name":"Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, 34094 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5977-7274","authenticated-orcid":false,"given":"Philippe","family":"Marin","sequence":"additional","affiliation":[{"name":"Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, 34094 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7385-681X","authenticated-orcid":false,"given":"Carine","family":"B\u00e9camel","sequence":"additional","affiliation":[{"name":"Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, 34094 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s13023-020-01463-z","article-title":"Neurofibromatosis I and multiple sclerosis","volume":"15","author":"Bergqvist","year":"2020","journal-title":"Orphanet. 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