Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus

Cell Res. 2016 Jun;26(6):728-42. doi: 10.1038/cr.2016.48. Epub 2016 Apr 22.


Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2(-/y)) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2(-/y) mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2(-/y) mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Bridged Bicyclo Compounds / pharmacology
  • Caudate Nucleus / metabolism
  • Cholinergic Neurons / metabolism*
  • Disease Susceptibility
  • Gene Deletion
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Male
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Nicotine / pharmacology
  • Phenotype
  • Prosencephalon / metabolism
  • Rett Syndrome / complications
  • Rett Syndrome / metabolism*
  • Rett Syndrome / pathology*
  • Seizures / complications
  • Seizures / pathology
  • Signal Transduction / drug effects
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*


  • Benzamides
  • Bridged Bicyclo Compounds
  • Methyl-CpG-Binding Protein 2
  • PNU-282987
  • alpha7 Nicotinic Acetylcholine Receptor
  • Nicotine