Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory

Nat Neurosci. 2011 Jul 17;14(8):1001-8. doi: 10.1038/nn.2866.

Abstract

DNA methylation-dependent epigenetic mechanisms underlie the development and function of the mammalian brain. MeCP2 is highly expressed in neurons and functions as a molecular linker between DNA methylation, chromatin remodeling and transcription regulation. Previous in vitro studies have shown that neuronal activity-induced phosphorylation (NAIP) of methyl CpG-binding protein 2 (MeCP2) precedes its release from the Bdnf promoter and the ensuing Bdnf transcription. However, the in vivo function of this phosphorylation event remains elusive. We generated knock-in mice that lack NAIP of MeCP2 and found that they performed better in hippocampus-dependent memory tests, presented enhanced long-term potentiation at two synapses in the hippocampus and showed increased excitatory synaptogenesis. At the molecular level, the phospho-mutant MeCP2 protein bound more tightly to several MeCP2 target gene promoters and altered the expression of these genes. Our results suggest that NAIP of MeCP2 is required for modulating dynamic functions of the adult mouse brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Anesthetics, Local / pharmacology
  • Animals
  • Biophysics
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Disks Large Homolog 4 Protein
  • Electric Stimulation / methods
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Fear / physiology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Guanylate Kinases / metabolism
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Long-Term Potentiation / genetics
  • Long-Term Potentiation / physiology*
  • Maze Learning / physiology
  • Membrane Proteins / metabolism
  • Memory / physiology*
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice
  • Mice, Transgenic
  • Microscopy, Confocal
  • Nerve Tissue Proteins / metabolism
  • Neuronal Apoptosis-Inhibitory Protein / metabolism
  • Neurons / drug effects
  • Neurons / physiology*
  • Phosphopyruvate Hydratase / metabolism
  • Phosphorylation / genetics
  • Potassium Chloride / pharmacology
  • Serine / metabolism
  • Space Perception / physiology*
  • Swimming / psychology
  • Synapses / genetics
  • Synapses / physiology*
  • Tetrodotoxin / pharmacology
  • Vesicular Glutamate Transport Protein 2 / metabolism

Substances

  • Anesthetics, Local
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Mecp2 protein, mouse
  • Membrane Proteins
  • Methyl-CpG-Binding Protein 2
  • Nerve Tissue Proteins
  • Neuronal Apoptosis-Inhibitory Protein
  • Slc17a6 protein, mouse
  • Vesicular Glutamate Transport Protein 2
  • Tetrodotoxin
  • Serine
  • Potassium Chloride
  • Guanylate Kinases
  • Phosphopyruvate Hydratase