Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus

Jonathan M Levenson,Tania L Roth,Farah D Lubin,Courtney A Miller,I-Chia Huang,Priyanka Desai,Lauren M Malone,J David Sweatt

doi:10.1074/jbc.m511767200

Jonathan M Levenson, Tania L Roth + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m511767200

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Abstract

DNA (cytosine-5) methylation represents one of the most widely used mechanisms of enduring cellular memory. Stable patterns of DNA methylation are established during development, resulting in creation of persisting cellular phenotypes. There is growing evidence that the nervous system has co-opted a number of cellular mechanisms used during development to subserve the formation of long term memory. In this study, we examined the role DNA (cytosine-5) methyltransferase (DNMT) activity might play in regulating the induction of synaptic plasticity. We found that the DNA within promoters for reelin and brain-derived neurotrophic factor, genes implicated in the induction of synaptic plasticity in the adult hippocampus, exhibited rapid and dramatic changes in cytosine methylation when DNMT activity was inhibited. Moreover, zebularine and 5-aza-2-deoxycytidine, inhibitors of DNMT activity, blocked the induction of long term potentiation at Schaffer collateral synapses. Activation of protein kinase C in the hippocampus decreased reelin promoter methylation and increased DNMT3A gene expression. Interestingly, DNMT activity is required for protein kinase C-induced increases in histone H3 acetylation. Considered together, these results suggest that DNMT activity is dynamically regulated in the adult nervous system and that DNMT may play a role in regulating the induction of synaptic plasticity in the mature CNS.

Highlights

Dividing cells and is very high during early development (5, 10 –13)
We found that inhibition of DNA (cytosine-5) methyltransferase (DNMT) alters DNA methylation within the promoter region of both reelin and BDNF1, indicating that acute regulation of DNA methylation occurs in the adult nervous system
We provide evidence that PKC-mediated changes in histone H3 acetylation are sensitive to DNMT activity. These findings provide the first evidence for DNA methylation in dynamic signaling in the adult nervous system and suggest that DNMT activity is required for normal hippocampal synaptic plasticity

Summary

Introduction

Dividing cells and is very high during early development (5, 10 –13). In most cell types, DNMT expression diminishes greatly once terminal differentiation occurs (5, 10 –14). Other studies have implicated the histone acetyltransferase CREB-binding protein in formation of hippocampus-dependent long term memory [25,26,27]. We hypothesize that direct modification of DNA, in the form of DNA (cytosine-5) methylation, is another epigenetic mechanism for long term information storage in the nervous system. In support of this hypothesis, previous studies have observed decreases in methylation of BDNF3 (rat) and BDNF4 (mouse) promoters in response to depolarization [33, 34]. Long term potentiation (LTP) of hippocampal Schaffer collateral synapses has received a great deal of experimental attention, since this form of synaptic plasticity utilizes many of the same

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