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

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. DNA (cytosine-5) methyltransferases (DNMTs)5 are a family of enzymes that catalyze the methylation of cytosine residues (1-5). Many biological processes, including imprinting, differentiation, X-chromosome inactivation, and long term transcriptional regulation, involve cytosine methylation, a covalent modification of DNA (6, 7). Tissue-specific patterns of DNA methylation are established early during development as a consequence of cellular differentiation (8, 9). Expression and activity of DNMT is generally restricted to 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).The mammalian brain consists primarily of postmitotic neurons and glial cells that possess relatively low proliferative potential. In addition, there are small populations of stem cells in various regions of the brain that have the potential to develop into new neurons (15). Therefore, reports that the adult central nervous system (CNS) possesses relatively high levels of DNMT mRNA and enzyme activity were surprising (5, 13, 16). Early studies into the function of DNMT in the brain suggested that this enzyme might be involved in DNA repair and neurodegeneration (16 -19). Important recent studies also have implicated misregulation of DNMT specifically or DNA methylation in general in such cognitive disorders as schizophrenia, Rett syndrome, and Fragile X mental retardation (20 -22).Epigenetics refers to a set of self-perpetuating post-translational modifications of DNA and nuclear proteins that produce lasting alterations in ch...

The social environment and the epigenome

“…One line of evidence comes from studies of epigenetic changes during long-term potentiation and fear conditioning by Sweat's group [Levenson et al, 2006;Miller and Sweatt, 2007] and the other line of evidence is our study of epigenetic programming by maternal care .…”

“…In the first set of experiments they have shown that treatment of nondividing neurons in hippocampal slices in culture with a protein kinase c activator phorbol-12,13-diacetate results in rapid increase in histone acetylation and demethylation of the reelin gene, a gene implicated in synaptic plasticity and learning [Levenson et al, 2006]. This is evidence that active demethylation activity is present in postmitotic neurons.…”

Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms

“…These covalent modifications of DNA and histone proteins regulate the degree of compaction or relaxation of chromatin, and permit or restrict access of regulatory molecules to DNA. Biological processes related to epigenetics include gene transcriptional regulation, imprinting, X-chromosome inactivation, pluripotency, differentiation, noncoding RNA function, and synaptic plasticity [20,22]. DNA methylation, the topic of this review, is the major direct modification of eukaryotic DNA and is known to have profound effects on the regulation of gene expression [20,[23][24][25].…”

“…Our discovery that Dnmt3a, but not Dnmt1, is located in presynaptic axon terminals in the adult CNS is exciting because it identifies a local presynaptic possibility for Dnmt3a in regulating synaptic function. Studies have shown that Dnmts function in synaptic plasticity [22,71] and behavioral plasticity [72]. Mice with conditional knockout of Dnmt1 and Dnmt3a, and with hypomethylation in forebrain show deficits in learning and memory distinct from single knockout mice, which show similar changes on behavioral tasks, suggesting that Dnmt1 and Dnmt3a have some overlapping functions in neurons [73].…”

“…DNA methylation appears to function in synaptic plasticity [22,71]. DNA methylation is a dynamic gene regulatory mechanism, as illustrated by some genes undergoing cyclical changes within minutes to hours [100].…”