How the epigenome integrates information and reshapes the synapse

Abstract

In the past few decades, the field of neuroepigenetics has investigated how the brain encodes information to form long-lasting memories that lead to stable changes in behaviour. Activity-dependent molecular mechanisms, including, but not limited to, histone modification, DNA methylation and nucleosome remodelling, dynamically regulate the gene expression required for memory formation. Recently, the field has begun to examine how a learning experience is integrated at the level of both chromatin structure and synaptic physiology. Here, we provide an overview of key established epigenetic mechanisms that are important for memory formation. We explore how epigenetic mechanisms give rise to stable alterations in neuronal function by modifying synaptic structure and function, and highlight studies that demonstrate how manipulating epigenetic mechanisms may push the boundaries of memory.

Fig. 1 |. regulation of synaptic plasticity-related gene expression through epigenetic mechanisms.

Several epigenetic mechanisms have been identified as regulators of gene expression important for synaptic plasticity and memory formation. For instance, histone acetylation mediated by the activity of histone acetyltransferases, such as CREB-binding protein (CBP), can facilitate memory-related gene expression. CBP is recruited by the transcription factor cAMP-responsive element-binding protein 1 (CREB1) and promotes a permissive transcription environment by adding acetyl groups onto the lysine tails of histones. By contrast, histone deacetylases (HDACs) remove acetyl groups from histone tails and act in concert with associated co-repressor transcription factors to reduce gene expression (for example, transcriptional co-repressor SIN3A). Gene expression can be repressed by the interaction with epigenetic enzymes, such as HDAC–repressor complexes or methyl-CpG-binding protein 2 (MeCP2), which binds to methylated DNA. DNA methylation is controlled by several DNA-modifying enzymes, including DNA methyltransferase 3A (DNMT3A) or DNMT3B and ten-eleven translocation enzymes (TETs), which reportedly repress or permit gene expression depending on the region of DNA that is methylated. Nucleosome-remodelling complexes, such as the neuronal BRG1-associated factor (nBAF) complex, interact with DNA and histones to potentially regulate chromatin structure and synapse-related gene expression through insertion of histone variants, nucleosome sliding, nucleosome eviction and chromatin looping. Although RNA-modifying enzymes do not directly affect chromatin structure, they do influence the rate of mRNA translation and the localization of RNAs, including at the synapse.

Fig. 2 |. synaptic plasticity and interactions between the epigenome and synapse.

a | Dendritic spines are filopodia-actin (F-actin)-rich protrusions that receive information from neighbouring cells via several types of surface receptor (left). The strength of synaptic transmission correlates with the size of dendritic spines. Synapses undergo changes in actin polymerization to rapidly expand the dendritic spine head and translocate synaptic proteins (middle). Multiple signalling cascades are activated to facilitate different aspects of synaptic plasticity. First, the activation of the ionotropic NMDA receptor (NMDAR) initiates several calcium-dependent signalling cascades important for regulation of synaptic protein activity and nuclear transcription. Second, the interaction of presynaptic neurexin and postsynaptic neuroligin cell adhesion molecules stabilizes transient synaptic contacts for synapse specification. Third, integrin receptors detect extracellular matrix (ECM) signals and promote the disassembly of cytoskeleton proteins. One downstream integrin mechanism is the activation of cofilin or other actin-related proteins (ARPs), which leads to the depolymerization and reorganization of actin filaments. Fourth, AMPA receptors (AMPARs) are trafficked to the postsynaptic density (PSD). Together, these mechanisms rebuild the dendritic spine head, increase the concentration of glutamatergic receptors and regulate the translocation of synaptic proteins (right). b | Following neuronal stimulation, synaptic proteins can translocate to the nucleus or induce signalling cascades to promote transcription. Although the time points are not fully characterized, epigenetic regulation of transcription is proposed to regulate memory and synaptic plasticity. It is hypothesized that epigenetic mechanisms alter chromatin structure to permit transcription of genes crucial for immediate cellular responses (such as immediate-early genes) and synaptic potentiation. Evidence suggests that synaptic proteins can translocate and interact with epigenetic modifiers to potentially also induce long-lasting changes in gene regulation. Along these same lines, epigenetic mechanisms regulate the expression of synapse-related genes (for example, genes important for cytoskeleton polymerization) and thus influence synaptic structure and function. In order to fully understand how changes to the epigenome and synapse lead to long-lasting changes in behaviour, it is critical to further explore how bidirectional interactions between the synapse and nucleus occur to persistently alter neuronal function. CBP, CREB-binding protein; CREB, cAMP-responsive element-binding protein; CRTC1, CREB-regulated transcriptional co-activator 1; GluR, glutamate receptor; nBAF, neuronal BRG1-associated factor.