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Motor function depends on not only central motor commands but also sensory feedback that is vulnerable to changes in excitability of propriosensory neurons. Here we report evidence for hyperexcitability of mesencephalic trigeminal (Me5) neurons in <jats:italic>Mecp2<\/jats:italic>\u2010null mice and a novel cellular mechanism for lowering its impact. In in vitro brain slices, the Me5 neurons in both <jats:italic>Mecp2<\/jats:italic><jats:sup>\u2212\/Y<\/jats:sup> male and symptomatic <jats:italic>Mecp2<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> female mice were overly excitable showing increased firing activity in comparison to their wild\u2010type (WT) male and asymptomatic counterparts. In <jats:italic>Mecp2<\/jats:italic><jats:sup>\u2212\/Y<\/jats:sup> males, Me5 neurons showed a reduced firing threshold. Consistently, the steady\u2010state activation of voltage\u2010gated Na<jats:sup>+<\/jats:sup> currents (I<jats:sub>Na<\/jats:sub>) displayed a hyperpolarizing shift in the <jats:italic>Mecp2<\/jats:italic>\u2010null neurons with no change in the I<jats:sub>Na<\/jats:sub> density. This seems to be due to NaV1.1, SCN1B and SCN4B overexpression and NaV1.2 and SCN3B under\u2010expression. In contrast to the hyperexcitability, the sag potential and postinhibitory rebound (PIR) were reduced in <jats:italic>Mecp2<\/jats:italic>\u2010null mice. In voltage\u2010clamp, the I<jats:sub>H<\/jats:sub> density was deficient by \u223c33%, and the steady\u2010state half\u2010activation had a depolarizing shift of \u223c10\u2009mV in the <jats:italic>Mecp2<\/jats:italic>\u2010null mice. Quantitative PCR analysis indicated that HCN2 was decreased, HCN1 was upregulated with no change in HCN4 in <jats:italic>Mecp2<\/jats:italic><jats:sup>\u2212\/Y<\/jats:sup> mice compared to WT. Lastly, blocking I<jats:sub>H<\/jats:sub> reduced the firing rate much more in WT than in <jats:italic>Mecp2<\/jats:italic>\u2010null neurons. These data suggest that the <jats:italic>Mecp2<\/jats:italic> defect causes an increase in Me5 neuronal excitability likely attributable to alterations in I<jats:sub>Na<\/jats:sub>, meanwhile I<jats:sub>H<\/jats:sub> is reduced likely altering neuronal excitability as well. J. Cell. Physiol. 232: 1151\u20131164, 2017. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.25589","type":"journal-article","created":{"date-parts":[[2016,9,27]],"date-time":"2016-09-27T05:26:10Z","timestamp":1474953970000},"page":"1151-1164","source":"Crossref","is-referenced-by-count":19,"title":["Hyperexcitability of Mesencephalic Trigeminal Neurons and Reorganization of Ion Channel Expression in a Rett Syndrome Model"],"prefix":"10.1002","volume":"232","author":[{"given":"Max F.","family":"Oginsky","sequence":"first","affiliation":[{"name":"Department of Biology Georgia State University Atlanta Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningren","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University Atlanta Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Biology 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