Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation.
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.
Nelson
Erika D
ED
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
Kavalali
Ege T
ET
Monteggia
Lisa M
LM
D000818:Animals; D000831:Animals, Newborn; D001374:Azacitidine / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006624:Hippocampus / Q000166:cytology; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D012333:RNA, Messenger; D016202:N-Methylaspartate; D011189:Potassium Chloride; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine