MeCP2 phosphorylation limits psychostimulant-induced behavioral and neuronal plasticity

Jie V. Deng, Yehong Wan, Xiaoting Wang, Sonia Cohen, William C. Wetsel, Michael E. Greenberg, Paul J. Kenny, Nicole Calakos, Anne E. West

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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.

Original languageEnglish
Pages (from-to)4519-4527
Number of pages9
JournalJournal of Neuroscience
Issue number13
StatePublished - 2014


  • Cocaine self-administration
  • GABAergic interneurons
  • Intrinsic excitability
  • MeCP2
  • Nucleus accumbens
  • Psychostimulants


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