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Abstract
Over the past decade, since epigenetic mechanisms were first implicated in memory formation and synaptic plasticity, dynamic DNA methylation reactions have been identified as integral to long-term memory formation, maintenance, and recall. This review incorporates various new findings that DNA methylation mechanisms are important regulators of non-Hebbian plasticity mechanisms, suggesting that these epigenetic mechanisms are a fundamental link between synaptic plasticity and metaplasticity. Because the field of neuroepigenetics is so young and the biochemical tools necessary to probe gene-specific questions are just now being developed and used, this review also speculates about the direction and potential of therapeutics that target epigenetic mechanisms in the central nervous system and the unique pharmacokinetic and pharmacodynamic properties that epigenetic therapies may possess. Mapping the dynamics of the epigenome in response to experiential learning, even a single epigenetic mark in isolation, remains a significant technical and bioinformatic hurdle facing the field, but will be necessary to identify changes to the methylome that govern memory-associated gene expression and effectively drug the epigenome.
Acknowledgements
We thank Lynn A. Mandeltort, Mikael C. Guzman Karlsson, Garrett Kaas, Kim Hawkins, and the other members of the Sweatt lab for stimulating discussion. This work is dedicated to the memory of Kindal Kivisto.
Declaration of interest
The authors report no declarations of competing interests. This work was supported by MH104158, MH57014, MH091122, Civitan International, the Evelyn F. McKnight Brain Research Foundation, and the Pitt-Hopkins Syndrome (PTHS) Foundation (JDS). A.J.K. is supported by the PTHS Foundation.