Epigenetic regulation and chromatin remodeling in learning and memory

Abstract

Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. Memory formation and maintenance are tightly controlled complex processes. Among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. Epigenetic regulation of the genome involves processes such as DNA methylation and histone post-translational modifications. These processes edit genomic properties or the interactions between the genome and histone cores. They then induce structural changes in the chromatin and lead to transcriptional changes of different genes. Recent studies have focused on the concept of chromatin remodeling, which consists of 3D structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. In this review, we will introduce three major epigenetic processes involved in memory regulation: DNA methylation, histone methylation and histone acetylation. We will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. Finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms.

Figure 1

Schematic drawing of histone methylation and acetylation in relation to chromatin remodeling. Addition of methyl groups to the tails of histone core proteins leads to histone methylation, which in turn leads to the adoption of a condensed state of chromatin called ‘heterochromatin.' Heterochromatin blocks transcription machinery from binding to DNA and results in transcriptional repression. The addition of acetyl groups to lysine residues in the N-terminal tails of histones causes histone acetylation, which leads to the adoption of a relaxed state of chromatin called ‘euchromatin.' In this state, transcription factors and other proteins can bind to their DNA binding sites and proceed with active transcription.

Figure 2

Illustration of late-LTP (L-LTP)_mechanism. Memory allocation involves several brain regions, including the hippocampus. As neurons in this region are recruited to store the memory trace, hippocampal CA1 region pyramidal cells undergo structural changes at the dendritic level and form new synaptic connections. Synaptic transmission involves pre-synaptic glutamate release in the gap junction and post-synaptic N-methyl-D-aspartate and AMPA receptor activation and downstream signaling cascades. The influx of Ca²⁺ through N-methyl-D-aspartate receptors into the cytoplasm activates CaMKII, which then activates protein kinase A (PKA) and mitogen-activated protein kinase (MAPK). Activated MAPK then induces CREB-mediated transcription in the nucleus, as CREB is a transcription factor that can lead to the synthesis of proteins, such as BDNF, c-fos and tyrosine hydroxylase. At dendritic sites, local translation independent of somatic transcription is also important for the enhancement of synaptic strength. Altogether, newly synthesized proteins are involved in processes such as receptor trafficking and cytoskeletal scaffolding, which contribute to AMPA receptor insertion and neurotransmitter responsiveness. These morphological changes enable L-LTP maintenance, which is thought to be the cellular basis for memory storage.