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The Journal of Neuroscience, January 9, 2008, 28(2):395-406; doi:10.1523/JNEUROSCI.3796-07.2008

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Cellular/Molecular
Activity-Dependent Suppression of Miniature Neurotransmission through the Regulation of DNA Methylation

Erika D. Nelson,¹ Ege T. Kavalali,^2,3 and Lisa M. Monteggia¹

Departments of ¹Psychiatry, ²Neuroscience, and ³Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070

Correspondence should be addressed to either of the following: Dr. Lisa M. Monteggia, Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, Email: lisa.monteggia{at}utsouthwestern.edu; or Dr. Ege T. Kavalali, Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9111, Email: ege.kavalali{at}utsouthwestern.edu

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.

Key words: spontaneous neurotransmission; MeCP2; hippocampal neuron; FM1-43; S-adenosyl-L-methionine; homeostatic plasticity

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Received Aug. 20, 2007; revised Nov. 9, 2007; accepted Nov. 14, 2007.

Correspondence should be addressed to either of the following: Dr. Lisa M. Monteggia, Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, Email: lisa.monteggia{at}utsouthwestern.edu; or Dr. Ege T. Kavalali, Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9111, Email: ege.kavalali{at}utsouthwestern.edu

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