Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation

Erika D. Nelson, Ege T Kavalali, Lisa M Monteggia

Research output: Contribution to journalArticle

182 Scopus citations

Abstract

DNA methylation is an epigenetic mechanism that plays a critical role in the repression of gene expression. Here, we show that DNA methyltransferase (DNMT) inhibition in hippocampal neurons results in activity-dependent demethylation of genomic DNA and a parallel decrease in the frequency of miniature EPSCs (mEPSCs), which in turn impacts neuronal excitability and network activity. Treatment with DNMT inhibitors reveals an activity-driven demethylation of brain-derived neurotrophic factor promoter I, which is mediated by synaptic activation of NMDA receptors, because it is susceptible to AP-5, a blocker of NMDA receptors. The specific effect of DNMT inhibition on spontaneous excitatory neurotransmission requires gene transcription and is occluded in the absence of the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Interestingly, enhancing excitatory activity, in the absence of DNMT inhibitors, also produces similar decreases in DNA methylation and mEPSC frequency, suggesting a role for DNA methylation in the control of homeostatic synaptic plasticity. Furthermore, adding excess substrate for DNA methylation (S-adenosyl-L-methionine) rescues the suppression of mEPSCs by DNMT inhibitors in wild-type neurons, as well as the defect seen in MeCP2-deficient neurons. These results uncover a means by which NMDA receptor-mediated synaptic activity drives DNA demethylation within mature neurons and suppresses basal synaptic function.

Original languageEnglish (US)
Pages (from-to)395-406
Number of pages12
JournalJournal of Neuroscience
Volume28
Issue number2
DOIs
StatePublished - Jan 9 2008

Keywords

  • FM1-43
  • Hippocampal neuron
  • Homeostatic plasticity
  • MeCP2
  • S-adenosyl-L-methionine
  • Spontaneous neurotransmission

ASJC Scopus subject areas

  • Neuroscience(all)

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