{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:15:14Z","timestamp":1791411314188,"version":"4.3.3"},"reference-count":39,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2016,6,2]],"date-time":"2016-06-02T00:00:00Z","timestamp":1464825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Jessica Carr Fund"},{"name":"CHEO Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurogastroenterology Motil"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Rett syndrome (<jats:styled-content style=\"fixed-case\">RTT<\/jats:styled-content>) is a neurological disorder characterized by severe cognitive impairment, motor dyspraxia, and seizures. Rett syndrome arises predominantly from mutations in <jats:styled-content style=\"fixed-case\">MECP<\/jats:styled-content>2, the gene coding for methyl\u2010CpG\u2010binding protein 2 (Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2). Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2 is an important mediator of synaptic development and is essential in regulating homeostatic synaptic plasticity (<jats:styled-content style=\"fixed-case\">HSP<\/jats:styled-content>) in the brain. In addition to demonstrating central nervous system impairment, <jats:styled-content style=\"fixed-case\">RTT<\/jats:styled-content> patients also suffer from gastrointestinal (<jats:styled-content style=\"fixed-case\">GI<\/jats:styled-content>) dysmotility. We hypothesize that this is due to a similar impairment of plasticity\u2010dependent synaptic function in the enteric nervous system (<jats:styled-content style=\"fixed-case\">ENS<\/jats:styled-content>). We recently reported that Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2 is expressed in the <jats:styled-content style=\"fixed-case\">ENS<\/jats:styled-content>, providing evidence that neuronal dysfunction may mediate the <jats:styled-content style=\"fixed-case\">GI<\/jats:styled-content> pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Baseline measures of Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2\u2010<jats:styled-content style=\"fixed-case\">KO <\/jats:styled-content><jats:italic>vs<\/jats:italic> wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) <jats:styled-content style=\"fixed-case\">GI<\/jats:styled-content> neuronal nitric oxide synthase (<jats:styled-content style=\"fixed-case\">nNOS<\/jats:styled-content>) were assessed in tissue samples and <jats:italic>in vitro<\/jats:italic>. Experiments were carried out to measure <jats:styled-content style=\"fixed-case\">nNOS<\/jats:styled-content> in baseline <jats:italic>vs<\/jats:italic> activated plasticity states <jats:italic>in vitro<\/jats:italic>. Functional <jats:italic>in vivo<\/jats:italic> studies were carried out to determine whether Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2\u2010<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> mice reproduced the <jats:styled-content style=\"fixed-case\">RTT GI<\/jats:styled-content> hypomotility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Methyl\u2010CpG\u2010binding protein 2\u2010<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> mice reproduced the <jats:styled-content style=\"fixed-case\">GI<\/jats:styled-content> hypomotility seen in <jats:styled-content style=\"fixed-case\">RTT<\/jats:styled-content>. Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2\u2010<jats:styled-content style=\"fixed-case\">KO GI<\/jats:styled-content> tissue demonstrated elevated <jats:styled-content style=\"fixed-case\">nNOS<\/jats:styled-content> levels. Cultured <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> enteric neurons showed upregulation of <jats:styled-content style=\"fixed-case\">nNOS<\/jats:styled-content> following moderate, prolonged stimulation by hyperkalemia; neurons from Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2\u2010<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> mice failed to show this <jats:styled-content style=\"fixed-case\">nNOS<\/jats:styled-content> upregulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions &amp; Inferences<\/jats:title><jats:p>Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2 is required for proper <jats:styled-content style=\"fixed-case\">GI<\/jats:styled-content> motility and normal <jats:styled-content style=\"fixed-case\">nNOS<\/jats:styled-content> levels. Neuronal nitric oxide synthase imbalances could mediate the <jats:styled-content style=\"fixed-case\">GI<\/jats:styled-content> dysmotility seen in <jats:styled-content style=\"fixed-case\">RTT<\/jats:styled-content>. Disruption of Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2\u2010dependent <jats:styled-content style=\"fixed-case\">HSP<\/jats:styled-content> may be the basis for aberrant <jats:styled-content style=\"fixed-case\">nNOS<\/jats:styled-content> levels and hence <jats:styled-content style=\"fixed-case\">GI<\/jats:styled-content> dysmotility in Me<jats:styled-content style=\"fixed-case\">CP<\/jats:styled-content>2\u2010<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> and RTT.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.12873","type":"journal-article","created":{"date-parts":[[2016,6,2]],"date-time":"2016-06-02T13:09:58Z","timestamp":1464872998000},"page":"1723-1730","source":"Crossref","is-referenced-by-count":19,"title":["Activity and Me<scp>CP<\/scp>2\u2010dependent regulation of <scp>nNOS<\/scp> levels in enteric neurons"],"prefix":"10.1111","volume":"28","author":[{"given":"G.","family":"Wahba","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine Faculty of Medicine University of Ottawa Ottawa ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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