{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:07:03Z","timestamp":1785434823686,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,12]]},"group-title":"Neuroscience","reference-count":96,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T00:00:00Z","timestamp":1747008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/00e7vz537","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Harvard Brain Tissue Resource Center supported by Public Health Service","award":["HHSN-271-2013-00030"],"award-info":[{"award-number":["HHSN-271-2013-00030"]}]},{"name":"University of Maryland Brain Bank a tissue repository of the National Institutes of Health (NIH) NeuroBioBank"},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["R01MH124671"],"award-info":[{"award-number":["R01MH124671"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institute of Neurological Diseases and Stroke1","award":["R01NS031373"],"award-info":[{"award-number":["R01NS031373"]}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["R21MH102548"],"award-info":[{"award-number":["R21MH102548"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["R01MH113543"],"award-info":[{"award-number":["R01MH113543"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"award":["K01MH112983"],"award-info":[{"award-number":["K01MH112983"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01NS112171"],"award-info":[{"award-number":["R01NS112171"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  We have reported that levels of metabotropic glutamate receptor 7 (mGlu\n                  <jats:sub>7<\/jats:sub>\n                  ) are dramatically decreased in brain samples from Rett syndrome patients carrying truncation mutations in the\n                  <jats:italic>Methyl-CpG Binding Protein 2<\/jats:italic>\n                  (\n                  <jats:italic>MECP2<\/jats:italic>\n                  ) gene. Additionally, we identified decreases in mGlu\n                  <jats:sub>7<\/jats:sub>\n                  levels in\n                  <jats:italic>\n                    Mecp2\n                    <jats:sup>+\/-<\/jats:sup>\n                  <\/jats:italic>\n                  female mice and demonstrated that administration of a positive allosteric modulator (PAM) with activity at mGlu\n                  <jats:sub>7<\/jats:sub>\n                  corrected deficits in cognitive, social, and respiratory domains. Here, we expanded our studies to a larger cohort of RTT samples covering a range of mutations and evaluated expression of the three widely expressed group III mGlu receptors (mGlu\n                  <jats:sub>4,7<\/jats:sub>\n                  <jats:sub>and<\/jats:sub>\n                  <jats:sub>8<\/jats:sub>\n                  ). We found significant decreases in mGlu\n                  <jats:sub>7<\/jats:sub>\n                  , but not mGlu\n                  <jats:sub>4<\/jats:sub>\n                  or mGlu\n                  <jats:sub>8<\/jats:sub>\n                  , mRNA expression across this larger cohort; additionally, we identified a previously unknown and robust correlation in the expression of mGlu\n                  <jats:sub>4<\/jats:sub>\n                  and mGlu\n                  <jats:sub>8<\/jats:sub>\n                  in control individuals. Stratification of RTT patients into individuals with mutations that are clinically correlated with severe versus mild disease revealed statistically significant decreases in mGlu\n                  <jats:sub>7<\/jats:sub>\n                  expression only in patients with mutations that induce more severe symptoms. We then administered the PAM VU0422288 to mice modeling the mild R306C mutation (\n                  <jats:italic>\n                    Mecp2\n                    <jats:sup>R306C\/+<\/jats:sup>\n                  <\/jats:italic>\n                  ) and found a significant reduction in apneas induced by VU0422888 administration despite no decreases in mGlu\n                  <jats:sub>7<\/jats:sub>\n                  expression in the brainstem or cortex. These results provide the first evidence of potentially broad utility for mGlu\n                  <jats:sub>7<\/jats:sub>\n                  PAMs in reducing apneas in RTT patients.\n                <\/jats:p>","DOI":"10.1101\/2025.05.08.652716","type":"posted-content","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T04:30:13Z","timestamp":1747024213000},"source":"Crossref","is-referenced-by-count":0,"title":["Profiling metabotropic glutamate receptor 7 expression in Rett syndrome: consequences for pharmacotherapy"],"prefix":"10.64898","author":[{"given":"Sheryl Anne D.","family":"Vermudez","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geanne A.","family":"Freitas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mackenzie","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Neuroscience, Loyola University Chicago, IL 60660, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocco","family":"Gogliotti","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Neuroscience, Loyola University Chicago, IL 60660, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen M.","family":"Niswender","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232"},{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232"},{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232"},{"name":"Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041121303055000_2025.05.08.652716v1.1","first-page":"206","article-title":"Safety and efficacy of trofinetide in Rett syndrome: a systematic review and meta-analysis of randomized controlled trials","volume":"241","year":"2024","journal-title":"BMC Pediatr"},{"key":"2026041121303055000_2025.05.08.652716v1.2","doi-asserted-by":"crossref","unstructured":"Akol, I. , F. 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