MeCP2 phosphorylation limits psychostimulant-induced behavioral and neuronal plasticity

J Neurosci. 2014 Mar 26;34(13):4519-27. doi: 10.1523/JNEUROSCI.2821-13.2014.

Abstract

The methyl-DNA binding protein MeCP2 is emerging as an important regulator of drug reinforcement processes. Psychostimulants induce phosphorylation of MeCP2 at Ser421; however, the functional significance of this posttranslational modification for addictive-like behaviors was unknown. Here we show that MeCP2 Ser421Ala knock-in mice display both a reduced threshold for the induction of locomotor sensitization by investigator-administered amphetamine and enhanced behavioral sensitivity to the reinforcing properties of self-administered cocaine. These behavioral differences were accompanied in the knock-in mice by changes in medium spiny neuron intrinsic excitability and nucleus accumbens gene expression typically observed in association with repeated exposure to these drugs. These data show that phosphorylation of MeCP2 at Ser421 functions to limit the circuit plasticities in the nucleus accumbens that underlie addictive-like behaviors.

Keywords: GABAergic interneurons; MeCP2; cocaine self-administration; intrinsic excitability; nucleus accumbens; psychostimulants.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / administration & dosage
  • Corpus Striatum / cytology
  • Dopamine Uptake Inhibitors / administration & dosage
  • Exploratory Behavior / drug effects*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • In Vitro Techniques
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / genetics*
  • Neurons / drug effects*
  • Phosphorylation / physiology
  • Self Administration

Substances

  • Central Nervous System Stimulants
  • Dopamine Uptake Inhibitors
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Amphetamine
  • Cocaine