{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:40:54Z","timestamp":1785436854189,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,31]]},"group-title":"Neuroscience","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01MH124671"],"award-info":[{"award-number":["R01MH124671"]}],"id":[{"id":"https:\/\/ror.org\/05xj56w78","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01NS031373,"],"award-info":[{"award-number":["R01NS031373,"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21MH102548"],"award-info":[{"award-number":["R21MH102548"]}],"id":[{"id":"https:\/\/ror.org\/05xj56w78","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01MH113543"],"award-info":[{"award-number":["R01MH113543"]}],"id":[{"id":"https:\/\/ror.org\/05xj56w78","id-type":"ROR","asserted-by":"publisher"}]},{"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"}]},{"id":[{"id":"https:\/\/ror.org\/00e7vz537","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HHSN-271-2013-00030"],"award-info":[{"award-number":["HHSN-271-2013-00030"]}],"id":[{"id":"https:\/\/ror.org\/05xf94514","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/00sde4n60","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Rett syndrome (RTT) and\n                  <jats:italic>MECP2<\/jats:italic>\n                  Duplication syndrome (MDS) are disorders caused by reciprocal decreases and increases in the expression of the transcriptional regulator,\n                  <jats:italic>Methyl CpG Binding Protein 2<\/jats:italic>\n                  (\n                  <jats:italic>MeCP2<\/jats:italic>\n                  ). We previously performed an mRNA expression profiling study of the temporal cortex region from patients diagnosed with RTT and corresponding age, postmortem interval, and sex-matched controls. These studies identified a significant reduction in the expression of the histamine H\n                  <jats:sub>3<\/jats:sub>\n                  receptor (\n                  <jats:italic>HRH3<\/jats:italic>\n                  ). In the current manuscript, we expanded this H\n                  <jats:sub>3<\/jats:sub>\n                  receptor profiling to additional RTT patient brain samples representing distinct\n                  <jats:italic>MECP2<\/jats:italic>\n                  mutations and confirmed significantly reduced levels of H\n                  <jats:sub>3<\/jats:sub>\n                  receptor expression in the majority of patients compared to controls. Using mouse models of RTT and MDS, we observed antiparallel changes in H\n                  <jats:sub>3<\/jats:sub>\n                  receptor expression across various brain areas, with\n                  <jats:italic>Hrh3<\/jats:italic>\n                  expression being reduced in RTT model animals and increased in a mouse model of MDS. We then evaluated both a small molecule agonist of the H\n                  <jats:sub>3<\/jats:sub>\n                  receptor, (\n                  <jats:italic>R<\/jats:italic>\n                  )-\u03b1-methylhistamine (RAMH), and the H\n                  <jats:sub>3<\/jats:sub>\n                  receptor inverse agonist, pitolisant (Wakix\u00ae), in RTT and MDS models, respectively, to determine impacts on phenotypes in these disease models. Our results show that RAMH significantly impacted an anxiety phenotype in mice modeling RTT (\n                  <jats:italic>\n                    Mecp\n                    <jats:sup>Null\/+<\/jats:sup>\n                  <\/jats:italic>\n                  ), but pitolisant had no effect on the behaviors examined here in MDS animals (\n                  <jats:italic>\n                    MECP2\n                    <jats:sup>Tg1<\/jats:sup>\n                  <\/jats:italic>\n                  ).\n                <\/jats:p>","DOI":"10.1101\/2025.10.30.685636","type":"posted-content","created":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:05:18Z","timestamp":1761955518000},"source":"Crossref","is-referenced-by-count":0,"title":["Reciprocal regulation of the H\n                  <sub>3<\/sub>\n                  histamine receptor in Rett syndrome and\n                  <i>MECP2<\/i>\n                  Duplication syndrome: implications for therapeutic development"],"prefix":"10.64898","author":[{"given":"Kelly","family":"Weiss","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232 (KW, SADV, GF, SD, MJM, RGG, CMN)"},{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232 (CMN)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheryl A. D.","family":"Vermudez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232 (KW, SADV, GF, SD, MJM, RGG, CMN)"},{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232 (CMN)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geanne","family":"Freitas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232 (KW, SADV, GF, SD, MJM, RGG, CMN)"},{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232 (CMN)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini","family":"Dogra","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232 (KW, SADV, GF, SD, MJM, RGG, CMN)"},{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232 (CMN)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mac J.","family":"Meadows","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232 (KW, SADV, GF, SD, MJM, RGG, CMN)"},{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232 (CMN)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocco G.","family":"Gogliotti","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232 (KW, SADV, GF, SD, MJM, RGG, CMN)"},{"name":"Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232 (CMN)"},{"name":"Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232 (CMN)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen 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