Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus.
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.
Levenson
Jonathan M
JM
Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Roth
Tania L
TL
Lubin
Farah D
FD
Miller
Courtney A
CA
Huang
I-Chia
IC
Desai
Priyanka
P
Malone
Lauren M
LM
Sweatt
J David
JD
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D017931:DNA Primers; D006624:Hippocampus / Q000201:enzymology / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D000091042:Reelin Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D000091042:Reelin Protein; D004248:DNA (Cytosine-5-)-Methyltransferases; D011493:Protein Kinase C; C000717128:Reln protein, mouse