QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

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

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Nelson, E. D. Articles by Monteggia, L. M. Search for Related Content PubMed PubMed Citation Articles by Nelson, E. D. Articles by Monteggia, L. M.

 Previous Article  |  Next Article 

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

---

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

This article has been cited by other articles:

				L. K. Hutnick, P. Golshani, M. Namihira, Z. Xue, A. Matynia, X. W. Yang, A. J. Silva, F. E. Schweizer, and G. Fan DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation Hum. Mol. Genet., August 1, 2009; 18(15): 2875 - 2888. [Abstract] [Full Text] [PDF]

				M. W. Akhtar, J. Raingo, E. D. Nelson, R. L. Montgomery, E. N. Olson, E. T. Kavalali, and L. M. Monteggia Histone Deacetylases 1 and 2 Form a Developmental Switch That Controls Excitatory Synapse Maturation and Function J. Neurosci., June 24, 2009; 29(25): 8288 - 8297. [Abstract] [Full Text] [PDF]

				M. Adachi, A. E. Autry, H. E. Covington III, and L. M. Monteggia MeCP2-Mediated Transcription Repression in the Basolateral Amygdala May Underlie Heightened Anxiety in a Mouse Model of Rett Syndrome J. Neurosci., April 1, 2009; 29(13): 4218 - 4227. [Abstract] [Full Text] [PDF]

				Y. Jiang, B. Langley, F. D. Lubin, W. Renthal, M. A. Wood, D. H. Yasui, A. Kumar, E. J. Nestler, S. Akbarian, and A. C. Beckel-Mitchener Epigenetics in the Nervous System J. Neurosci., November 12, 2008; 28(46): 11753 - 11759. [Abstract] [Full Text] [PDF]

				F. D. Lubin, T. L. Roth, and J. D. Sweatt Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Fear Memory J. Neurosci., October 15, 2008; 28(42): 10576 - 10586. [Abstract] [Full Text] [PDF]

				N. Mellios, H.-S. Huang, A. Grigorenko, E. Rogaev, and S. Akbarian A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex Hum. Mol. Genet., October 1, 2008; 17(19): 3030 - 3042. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help