title: Activity and MeCP2-dependent regulation of nNOS levels in enteric neurons.
abstract: BACKGROUND
  Rett syndrome (RTT) is a neurological disorder characterized by severe cognitive impairment, motor dyspraxia, and seizures. Rett syndrome arises predominantly from mutations in MECP2, the gene coding for methyl-CpG-binding protein 2 (MeCP2). MeCP2 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 MeCP2 is expressed in the ENS, providing evidence that neuronal dysfunction may mediate the GI pathology.
  
  
  METHODS
  Baseline measures of MeCP2-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 MeCP2-KO mice reproduced the RTT GI hypomotility.
  
  
  RESULTS
  Methyl-CpG-binding protein 2-KO mice reproduced the GI hypomotility seen in RTT. MeCP2-KO GI tissue demonstrated elevated nNOS levels. Cultured WT enteric neurons showed upregulation of nNOS following moderate, prolonged stimulation by hyperkalemia; neurons from MeCP2-KO mice failed to show this nNOS upregulation.
  
  
  CONCLUSIONS
  MeCP2 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 MeCP2-dependent HSP may be the basis for aberrant nNOS levels and hence GI dysmotility in MeCP2-KO and RTT.
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Wahba
authors.affiliation: Research Institute, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
authors.forename: S C
authors.initials: SC
authors.lastname: Schock
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Cudd
authors.affiliation: Department of Pathology, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Grynspan
authors.affiliation: Division of Neurology, Department of Paediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Humphreys
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. wstaines@uottawa.ca.
authors.forename: W A
authors.initials: WA
authors.lastname: Staines
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017615:Enteric Nervous System / Q000378:metabolism* / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism* / Q000503:physiopathology; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D015518:Rett Syndrome / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: MeCP2; Rett syndrome; gastrointestinal; homeostatic synaptic plasticity; nitric oxide