A clear understanding is developing concerning the importance of epigenetic-related
molecular mechanisms in transcription-dependent long-term memory formation. Chromatin
modification, in particular histone acetylation, is associated with transcriptional
activation, and acetylation of histone 3 (H3) occurs in Area CA1 of the hippocampus
following contextual fear conditioning training. Conversely, DNA methylation is associated
with transcriptional repression, but is also dynamically regulated in Area CA1 following
training. We recently reported that inhibition of the enzyme responsible for DNA methylation,
DNA methyltransferase (DNMT), in the adult rat hippocampus blocks behavioral memory
formation. Here, we report that DNMT inhibition also blocks the concomitant memory-associated
H3 acetylation, without affecting phosphorylation of its upstream regulator, extracellular
signal-regulated kinase (ERK). Interestingly, the DNMT inhibitor-induced deficit in
memory consolidation, along with deficits in long-term potentiation, can be rescued
by pharmacologically increasing levels of histone acetylation prior to DNMT inhibition.
These observations suggest that DNMT activity is not only necessary for memory and
plasticity, but that DNA methylation may work in concert with histone modifications
to regulate plasticity and memory formation in the adult rat hippocampus.