Signaling Mechanisms Linking Neuronal Activity to Gene Expression and Plasticity of the Nervous System

Abstract

Sensory experience and the resulting synaptic activity within the brain are critical for the proper development of neural circuits. Experience-driven synaptic activity causes membrane depolarization and calcium influx into select neurons within a neural circuit, which in turn trigger a wide variety of cellular changes that alter the synaptic connectivity within the neural circuit. One way in which calcium influx leads to the remodeling of synapses made by neurons is through the activation of new gene transcription. Recent studies have identified many of the signaling pathways that link neuronal activity to transcription, revealing both the transcription factors that mediate this process and the neuronal activity-regulated genes. These studies indicate that neuronal activity regulates a complex program of gene expression involved in many aspects of neuronal development, including dendritic branching, synapse maturation, and synapse elimination. Genetic mutations in several key regulators of activity-dependent transcription give rise to neurological disorders in humans, suggesting that future studies of this gene expression program will likely provide insight into the mechanisms by which the disruption of proper synapse development can give rise to a variety of neurological disorders.

Environmental regulation of the neural epigenome

“…[69][70][71][72]). Calcium-dependent depolarization of hippocampal neurons leads to an increase in the transcription of the BDNF gene that associates with a decrease in the methylation of the exon IV promoter [80] (and see [81] for a review). BDNF is associated with LG mothers show increased hippocampal expression of NGFI-A (also referred to as zif-268, krox-24, and egr-1).…”

A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα

“…Synaptic activity induces a variety of changes in neurons, ranging from transient posttranslational modifications to modulation of gene expression programs 23 . The signals generated in synapses must therefore be transported to the nucleus, and it has been shown, in sensory neurons of mollusk Aplysia and hippocampal neurons of mice, that the classical nuclear import pathway plays a critical role in transporting synaptically generated signals into the nucleus during learning-related forms of plasticity 24 .…”

Voltage-Gated Calcium Channels

“…In neurons, voltage-gated Ca 2þ channels initiate synaptic transmission (Tsien et al 1988;Dunlap et al 1995;Catterall and Few 2008). In many different cell types, Ca 2þ entering the cytosol via voltage-gated Ca 2þ channels regulates enzyme activity, gene expression, and other biochemical processes (Flavell and Greenberg 2008). Thus, voltage-gated Ca 2þ channels are Since the first recordings of Ca 2þ currents in cardiac myocytes (reviewed in Reuter 1979), it has become apparent that there are multiple types of Ca 2þ currents as defined by physiological and pharmacological criteria (Tsien et al 1988;Bean 1989a;Llinás et al 1992).…”

“…L-type Ca 2þ currents are also recorded in endocrine cells where they initiate release of hormones (Yang and Berggren 2006) and in neurons where they are important in regulation of gene expression, integration of synaptic input, and initiation of neurotransmitter release at specialized ribbon synapses in sensory cells (Tsien et al 1988;Bean 1989a;Flavell and Greenberg 2008). L-type Ca 2þ currents are subject to regulation by second messenger-activated protein phosphorylation in several cell types as discussed below.…”

“…Ca 2þ entering neurons through L-type Ca 2þ currents conducted by Ca V 1 channels has a privileged role in regulation of gene transcription, compared to similar amounts of Ca 2þ entering via other voltage-gated or ligand-gated ion channels (Flavell and Greenberg 2008). This unique access of Ca V 1 channels to regulation of transcription might arise from preferential localization, which could provide Ca 2þ in the vicinity of transcriptional regulators, preferential interaction with binding partners, which could be activated by local Ca 2þ entry and carry the regulatory signal to the nucleus, or nuclear targeting of a subunit or domain of the Ca V 1 channel itself, which would serve to regulate transcription directly.…”