The role of histone acetylation in memory formation and cognitive impairments

Abstract

Long-term memory formation requires transcription and protein synthesis. Over the past few decades, a great amount of knowledge has been gained regarding the molecular players that regulate the transcriptional program linked to memory consolidation. Epigenetic mechanisms have been shown to be essential for the regulation of neuronal gene expression, and histone acetylation has been one of the most studied and best characterized. In this review, we summarize the lines of evidence that have shown the relevance of histone acetylation in memory in both physiological and pathological conditions. Great advances have been made in identifying the writers and erasers of histone acetylation marks during learning. However, the identities of the upstream regulators and downstream targets that mediate the effect of changes in histone acetylation during memory consolidation remain restricted to a handful of molecules. We outline a general model by which corepressors and coactivators regulate histone acetylation during memory storage and discuss how the recent advances in high-throughput sequencing have the potential to radically change our understanding of how epigenetic control operates in the brain.

Figure 1

Writers, Erasers, and Readers of histone marks during long-term memory formation. Molecules that regulate acetylation of histone tails can be conceptually grouped into three categories (Borrelli et al, 2008): Writers, the enzymes that are able to add acetyl groups to the lysines in the tails (KATs); Erasers, the enzymes that remove the acetyl groups (KDACs); and Readers, the proteins that possess bromodomains and can recognize acetylated lysines (including KATs). For details on the evidence linking listed writers, erasers, and readers, see Tables 2 and 3.

Figure 2

Regulation of gene expression by histone acetylation in the brain. On the left, a model of the proposed status of chromatin and corepressor complexes in basal state (low calcium) is presented, based on the data discussed in the review and the corepressor complexes known to regulate Nr4a1 expression. On the right, a model of the effect of neuronal activity and calcium influx on chromatin is presented, including coactivators. For simplicity, corepressor complexes are not depicted on the right; however, it is unclear whether they actually dissociate from chromatin.