Epigenetic regulation of memory formation and maintenance

Abstract

Understanding the cellular and molecular mechanisms underlying the formation and maintenance of memories is a central goal of the neuroscience community. It is well regarded that an organism's ability to lastingly adapt its behavior in response to a transient environmental stimulus relies on the central nervous system's capability for structural and functional plasticity. This plasticity is dependent on a well-regulated program of neurotransmitter release, post-synaptic receptor activation, intracellular signaling cascades, gene transcription, and subsequent protein synthesis. In the last decade, epigenetic markers like DNA methylation and post-translational modifications of histone tails have emerged as important regulators of the memory process. Their ability to regulate gene transcription dynamically in response to neuronal activation supports the consolidation of long-term memory. Furthermore, the persistent and self-propagating nature of these mechanisms, particularly DNA methylation, suggests a molecular mechanism for memory maintenance. In this review, we will examine the evidence that supports a role of epigenetic mechanisms in learning and memory. In doing so, we hope to emphasize (1) the widespread involvement of these mechanisms across different behavioral paradigms and distinct brain regions, (2) the temporal and genetic specificity of these mechanisms in response to upstream signaling cascades, and (3) the functional outcome these mechanisms may have on structural and functional plasticity. Finally, we consider the future directions of neuroepigenetic research as it relates to neuronal storage of information.

Figure 1.

General schematic of epigenetic modifications. (A) Packaging of DNA into chromatin is achieved through the wrapping of 146 bp of DNA around octamers of histone proteins. Chromatin-modifying enzymes dynamically regulate the addition and removal of post-translational modifications on histone N-terminal tails. Modifications associated with learning and memory include histone acetylation, phosphorylation, and methylation. The specific combination of histone tail modifications dictate whether or not the chromatin exists as heterochromatin or euchromatin. Heterochromatin is characterized by condensed chromatin and subsequent transcriptional repression. Euchromatin is characterized by a relaxed chromatin state that allows transcriptional machinery access to DNA for gene expression. (B) Methylation of DNA involves covalent addition of a methyl group to the 5′ position of the cytosine pyrimidine ring by DNMTs. DNA methylation commonly occurs at genes enriched with cytosine-guanine nucleotides (CpG islands). Proteins with methyl-binding domains, like MeCP2, bind to methylated DNA and recruit repressor complexes containing HDACs. Recent evidence suggests that active DNA demethylation can occur via several mechanisms involving members of the Gadd45 family, TET family, and DNMTs themselves. (DNMTs) DNA methyltransferases, (Gadd45) growth arrest and DNA damage 45, (HATs) histone acetyltransferases, (HDACs) histone deacetylases, (HDMs) histone demethylases, (HMTs) histone methyltransferases, (MeCP2) methyl CpG binding protein 2, (PKs) protein kinases, (PPs) protein phosphatases, (TETs) ten eleven translocation, (TF) transcription factor, (RNAP II) RNA polymerase II.

Figure 2.

A model depicting the role of epigenetic mechanisms in memory formation and maintenance. Environmental stimuli, which consist primarily of associative learning tasks in animal models, initiate cellular communication by activating specific post-synaptic receptors. Receptor activation stimulates specific intracellular signaling cascades that lead to particular patterns of epigenetic modifications, which in turn regulate the access of transcription factors (TF) and RNA polymerase II (RNA P II) to gene promoters. These regulatory processes result in an increased transcription of memory activator genes and decreased transcription of memory-suppressor genes, which ultimately promote memory formation and maintenance through effects on long-term potentiation (LTP), spine density, memory allocation, cell excitability, and metaplasticity.