Experience-dependent epigenetic modifications in the central nervous system

Abstract

This mini-review describes recent discoveries demonstrating that experience can drive the production of epigenetic marks in the adult nervous system and that the experience-dependent regulation of epigenetic molecular mechanisms in the mature central nervous system participates in the control of gene transcription underlying the formation of long-term memories. In the mammalian experimental systems investigated thus far, epigenetic mechanisms have been linked to associative fear conditioning, extinction of learned fear, and hippocampus-dependent spatial memory formation. Intriguingly, in one experimental system epigenetic marks at the level of chromatin structure (histone acetylation) have been linked to the recovery of memories that had seemed to be "lost" (i.e., not available for recollection). Environmental enrichment has long been known to have positive effects on memory capacity, and recent studies have suggested that these effects are at least partly due to the recruitment of epigenetic mechanisms by environmental enrichment. Finally, an uncoupling of signal transduction pathways from the regulation of epigenetic mechanisms in the nucleus has been implicated in the closure of developmental critical periods. Taken together, these eclectic findings suggest a new perspective on experience-dependent dynamic regulation of epigenetic mechanisms in the adult nervous system and their relevance to biological psychiatry.

Figure 1

The historical model with separate and distinct influences of genes and environment on behavior (Panel A) is now known to be over-simplified. Instead, contemporary studies have illustrated that environment and experience act in part through altering gene readout in the CNS in order to achieve their effects on behavior (Panel B). One component of the processes by which the environment and experience alter individual behavior includes epigenetic molecular mechanisms such as regulation of chromatin structure and DNA methylation. The historical dichotomy between “nature” (genes) and “nurture” (environment and experience) is too simplistic – genes and experience are mechanistically intertwined. Epigenetic molecular mechanisms contribute to this intertwining.

Figure 2

A simplified scheme for DNA methylation-dependent gene silencing. Methylation of cytosines at CpG dinucleotides (red lollipops) recruits methyl-DNA binding proteins locally to specific sites in the genome. All proteins that bind to methylated DNA have both a methyl-DNA binding domain (MBD) and a transcription-regulatory domain (TRD). The TRD recruits adapter proteins which in turn recruit histone de-acetylases (HDACs). The HDACs alter chromatin structure locally through removing acetyl groups (Ac) from histone core proteins (grey spheres), leading to compaction of chromatin and transcriptional suppression. It is important to note that while this is the traditional and well-established role of methyl-DNA binding proteins in transcriptional regulation, recent findings also support the idea that DNA methylation can also be associated with transcriptional activation.