Phosphorylation of MeCP2 at Ser421 contributes to chronic antidepressant action.

Journal Article (Journal Article)

Although tricyclic antidepressants rapidly activate monoaminergic neurotransmission, these drugs must be administered chronically to alleviate symptoms of depression. This observation suggests that molecular mechanisms downstream of monoamine receptor activation, which include the induction of gene transcription, underlie chronic antidepressant-induced changes in behavior. Here we show that methyl-CpG-binding protein 2 (MeCP2) regulates behavioral responses to chronic antidepressant treatment. Imipramine administration induces phosphorylation of MeCP2 at Ser421 (pMeCP2) selectively in the nucleus accumbens and the lateral habenula, two brain regions important for depressive-like behaviors. To test the role of pMeCP2 in depressive-like behaviors, we used male mice that bear a germ-line mutation knocked into the X-linked Mecp2 locus that changes Ser421 to a nonphosphorylatable Ala residue (S421A). MeCP2 S421A knock-in (KI) mice showed increased immobility in forced-swim and tail-suspension tests compared with their wild-type (WT) littermates. However, immobility of both MeCP2 WT and KI mice in forced swim was reduced by acute administration of imipramine, demonstrating that loss of pMeCP2 does not impair acute pharmacological sensitivity to this drug. After chronic social defeat stress, chronic administration of imipramine significantly improved social interaction in the MeCP2 WT mice. In contrast, the MeCP2 KI mice did not respond to chronic imipramine administration. These data suggest novel roles for pMeCP2 in the sensitivity to stressful stimuli and demonstrate that pMeCP2 is required for the effects of chronic imipramine on depressive-like behaviors induced by chronic social defeat stress.

Full Text

Duke Authors

Cited Authors

  • Hutchinson, AN; Deng, JV; Cohen, S; West, AE

Published Date

  • October 10, 2012

Published In

Volume / Issue

  • 32 / 41

Start / End Page

  • 14355 - 14363

PubMed ID

  • 23055506

Pubmed Central ID

  • PMC3480513

Electronic International Standard Serial Number (EISSN)

  • 1529-2401

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.2156-12.2012


  • eng

Conference Location

  • United States