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Activity and Me CP 2‐dependent regulation of nNOS levels in enteric neurons
Author(s) -
Wahba G.,
Schock S. C.,
Cudd S.,
Grynspan D.,
Humphreys P.,
Staines W. A.
Publication year - 2016
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.12873
Subject(s) - rett syndrome , downregulation and upregulation , synaptic plasticity , enteric nervous system , endocrinology , medicine , nitric oxide synthase , central nervous system , neuroscience , biology , nitric oxide , chemistry , receptor , biochemistry , gene
Background Rett syndrome ( RTT ) is a neurological disorder characterized by severe cognitive impairment, motor dyspraxia, and seizures. Rett syndrome arises predominantly from mutations in MECP 2, the gene coding for methyl‐CpG‐binding protein 2 (Me CP 2). Me CP 2 is an important mediator of synaptic development and is essential in regulating homeostatic synaptic plasticity ( HSP ) in the brain. In addition to demonstrating central nervous system impairment, RTT patients also suffer from gastrointestinal ( GI ) dysmotility. We hypothesize that this is due to a similar impairment of plasticity‐dependent synaptic function in the enteric nervous system ( ENS ). We recently reported that Me CP 2 is expressed in the ENS , providing evidence that neuronal dysfunction may mediate the GI pathology. Methods Baseline measures of Me CP 2‐ KO vs wild‐type ( WT ) GI neuronal nitric oxide synthase ( nNOS ) were assessed in tissue samples and in vitro . Experiments were carried out to measure nNOS in baseline vs activated plasticity states in vitro . Functional in vivo studies were carried out to determine whether Me CP 2‐ KO mice reproduced the RTT GI hypomotility. Key Results Methyl‐CpG‐binding protein 2‐ KO mice reproduced the GI hypomotility seen in RTT . Me CP 2‐ KO GI tissue demonstrated elevated nNOS levels. Cultured WT enteric neurons showed upregulation of nNOS following moderate, prolonged stimulation by hyperkalemia; neurons from Me CP 2‐ KO mice failed to show this nNOS upregulation. Conclusions & Inferences Me CP 2 is required for proper GI motility and normal nNOS levels. Neuronal nitric oxide synthase imbalances could mediate the GI dysmotility seen in RTT . Disruption of Me CP 2‐dependent HSP may be the basis for aberrant nNOS levels and hence GI dysmotility in Me CP 2‐ KO and RTT.