Transcriptional and epigenetic regulation of Hebbian and non-Hebbian plasticity

Abstract

The epigenome is uniquely positioned as a point of convergence, integrating multiple intracellular signaling cascades into a cohesive gene expression profile necessary for long-term behavioral change. The last decade of neuroepigenetic research has primarily focused on learning-induced changes in DNA methylation and chromatin modifications. Numerous studies have independently demonstrated the importance of epigenetic modifications in memory formation and retention as well as Hebbian plasticity. However, how these mechanisms operate in the context of other forms of plasticity is largely unknown. In this review, we examine evidence for epigenetic regulation of Hebbian plasticity. We then discuss how non-Hebbian forms of plasticity, such as intrinsic plasticity and synaptic scaling, may also be involved in producing the cellular adaptations necessary for learning-related behavioral change. Furthermore, we consider the likely roles for transcriptional and epigenetic mechanisms in the regulation of these plasticities. In doing so, we aim to expand upon the idea that epigenetic mechanisms are critical regulators of both Hebbian and non-Hebbian forms of plasticity that ultimately drive learning and memory.

Keywords: DNA methylation; Epigenetics; Hebbian; Histone modifications; Homeostatic; Intrinsic; Metaplasticity; Non-Hebbian; Synaptic; Synaptic scaling.

Figure 1. Induction and Expression Sites for Hebbian and non-Hebbian Forms of Plasticity

Hebbian plasticity involves the modulation of synaptic efficacy due to precise coordination of pre- and post-synaptic activity. In contrast, non-Hebbian forms of plasticity are not dependent on coincident activity. Hebbian and non-Hebbian plasticities are induced and expressed differently, suggesting each possesses specific functions in the memory process. (a) The modulation of synaptic efficacy in Hebbian plasticity is synapse-specific; as a result, the sites of induction (green) and expression (blue) are co-localized. Classically expression is thought to occur post-synaptically via trafficking of ligand-gated ionotropic receptors (e.g., AMPARs), although there is evidence for the involvement of presynaptic modifications. The throughput (red), or the ability of synaptic activity to elicit an action potential, is altered only at those synapses expressing changes in synaptic efficacy. (b) Intrinsic plasticity is a form of non-Hebbian plasticity where modulation of voltage- and calcium-gated ion channels regulates synaptic integration and action potential generation. There is evidence that changes in intrinsic plasticity can be induced by local synaptic activity (as shown) as well as global changes in action potential firing. Similarly, intrinsic plasticity can be expressed locally (restricted to a subset of distal dendrites) or globally (as shown; involving broader changes along the dendritic tree and/or the axo-somatic membrane). In the setting of global changes, there is potential for throughput of all synapses to be altered. (c) Synaptic scaling is a form of non-Hebbian plasticity involving the multiplicative modification of postsynaptic ligand-gated ionotropic receptor (e.g., AMPAR) density across all synapses. Such changes occur in response to a given neuron sensing chronic alterations in its own firing rate through variations in Ca²⁺ influx at the soma. Since modifications occur at all synapses the throughput of all synapses are changed. However, relative weights of preexisting synaptic changes are maintained since scaling occurs in a multiplicative fashion. Adapted from Zhang and Linden (2003).

Figure 2. Potential Shared Molecular Mechanisms of Transcriptional Regulation between Intrinsic Plasticity and Synaptic Scaling

Although clear distinctions exist in the induction and expression of intrinsic plasticity (IP) and synaptic scaling (SS), accumulating evidence suggests both plasticities rely on conserved molecular mechanisms also known to be involved in the long-term changes in gene expression necessary for Hebbian plasticity. Here we present a simplified model intended to demonstrate likely points of molecular convergence between IP and SS that require further experimental confirmation and elucidation. Despite differences in induction site (synaptic as in IP and somatic as in SS), there is a clear role for transcriptional regulation via Ca²⁺-mediated signaling. Ca²⁺ entry either through synaptic NMDA receptors or somatic voltage-gated calcium channels (VGGCs) directly and/or indirectly activates protein kinases like protein kinase C (PKC) and cAMP-dependent protein kinase (PKA) which converge on extracellular receptor kinase (ERK) and lead to its nuclear translocation. In SS, brain-derived neurotrophic factor (BDNF) binding of TrkB receptors likely serves as a level of higher-order control in the regulation of ERK nuclear translocation. Nuclear ERK may engage cAMP-response element (CREB)-mediated gene transcription through activation of downstream kinases such as mitogen- and stress-activated protein-kinase 1 (MSK1). Additionally, nuclear translocation of Ca²⁺/calmodulin (CaM) regulates Ca²⁺/calmodulin-dependent kinase IV (CaMKIV) activity, a key mediator of both CREB and CREB-binding protein (CBP) phosphorylation and activation. Furthermore, it is likely both IP and SS engage transcriptional repressors and small non-coding RNAs along with transcriptional activators like CREB. Coordinated expression of specific ion channels/receptors, associated trafficking proteins, and secondary messenger proteins will dictate how each form of plasticity manifests at the level of the cell membrane.