{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:10:57Z","timestamp":1753884657428,"version":"3.41.2"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T00:00:00Z","timestamp":1484870400000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01\u2010NS\u2010073875"],"award-info":[{"award-number":["R01\u2010NS\u2010073875"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2017,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Rett syndrome (<jats:styled-content style=\"fixed-case\">RTT<\/jats:styled-content>) is mostly caused by mutations of the X\u2010linked <jats:italic><jats:styled-content style=\"fixed-case\">MECP<\/jats:styled-content>2<\/jats:italic> gene. Although the causal neuronal mechanisms are still unclear, accumulating experimental evidence obtained from <jats:italic>Mecp2<\/jats:italic><jats:sup>\u2212\/Y<\/jats:sup> mice suggests that imbalanced excitation\/inhibition in central neurons plays a major role. Several approaches may help to rebalance the excitation\/inhibition, including agonists of <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content> receptors (<jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub>R<\/jats:styled-content>). Indeed, our previous studies have shown that early\u2010life exposure of <jats:italic>Mecp2<\/jats:italic>\u2010null mice to the extrasynaptic <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub>R<\/jats:styled-content> agonist <jats:styled-content style=\"fixed-case\">THIP<\/jats:styled-content> alleviates several <jats:styled-content style=\"fixed-case\">RTT<\/jats:styled-content>\u2010like symptoms including breathing disorders, motor dysfunction, social behaviors, and lifespan. However, how the chronic <jats:styled-content style=\"fixed-case\">THIP<\/jats:styled-content> affects the <jats:italic>Mecp2<\/jats:italic><jats:sup>\u2212\/Y<\/jats:sup> mice at the cellular level remains elusive. Here, we show that the <jats:styled-content style=\"fixed-case\">THIP<\/jats:styled-content> exposure in early lives markedly alleviated hyperexcitability of two types of brainstem neurons in <jats:italic>Mecp2<\/jats:italic><jats:sup>\u2212\/Y<\/jats:sup> mice. In neurons of the locus coeruleus (<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>), known to be involved in breathing regulation, the hyperexcitability showed clear age\u2010dependence, which was associated with age\u2010dependent deterioration of the <jats:styled-content style=\"fixed-case\">RTT<\/jats:styled-content>\u2010like breathing irregularities. Both the neuronal hyperexcitability and the breathing disorders were relieved with early <jats:styled-content style=\"fixed-case\">THIP<\/jats:styled-content> treatment. In neurons of the mesencephalic trigeminal nucleus (Me5), both the neuronal hyperexcitability and the changes in intrinsic membrane properties were alleviated with the <jats:styled-content style=\"fixed-case\">THIP<\/jats:styled-content> treatment in <jats:italic>Mecp2<\/jats:italic>\u2010null mice. The effects of <jats:styled-content style=\"fixed-case\">THIP<\/jats:styled-content> on both <jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content> and Me5 neuronal excitability remained 1\u00a0week after withdrawal. Persistent alleviation of breathing abnormalities in <jats:italic>Mecp2<\/jats:italic><jats:sup>\u2212\/Y<\/jats:sup> mice was also observed a week after <jats:styled-content style=\"fixed-case\">THIP<\/jats:styled-content> withdrawal. These results suggest that early\u2010life exposure to <jats:styled-content style=\"fixed-case\">THIP<\/jats:styled-content>, a potential therapeutic medicine, appears capable of controlling neuronal hyperexcitability in <jats:italic>Mecp2<\/jats:italic><jats:sup>\u2212\/Y<\/jats:sup> mice, which occurs in the absence of <jats:styled-content style=\"fixed-case\">THIP<\/jats:styled-content> in the recording solution, lasts at least 1\u00a0week after withdrawal, and may contribute to the <jats:styled-content style=\"fixed-case\">RTT<\/jats:styled-content>\u2010like symptom mitigation.<\/jats:p>","DOI":"10.14814\/phy2.13110","type":"journal-article","created":{"date-parts":[[2017,1,21]],"date-time":"2017-01-21T01:25:45Z","timestamp":1484961945000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effects of early\u2010life exposure to THIP on brainstem neuronal excitability in the <i>Mecp2<\/i>\u2010null mouse model of Rett syndrome before and after drug withdrawal"],"prefix":"10.14814","volume":"5","author":[{"given":"Weiwei","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Biology Georgia State University Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningren","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max F.","family":"Oginsky","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,1,20]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1012104107"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.22360"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09582"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2007.01.017"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/85899"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/jada.2003.50026"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00399.2012"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00109.2013"},{"key":"e_1_2_6_10_1","first-page":"02016","article-title":"Defects in brainstem neurons associated with breathing and motor function in the Mecp2R168X\/Y mouse model of Rett syndrome","volume":"00132","author":"Johnson C. 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