Activity-dependent plasticity and gene expression modifications in the adult CNS

Abstract

Information processing, memory formation, or functional recovery after nervous system damage depend on the ability of neurons to modify their functional properties or their connections. At the cellular/molecular level, structural modifications of neural circuits are finely regulated by intrinsic neuronal properties and growth-regulatory cues in the extracellular milieu. Recently, it has become clear that stimuli coming from the external world, which comprise sensory inflow, motor activity, cognitive elaboration, or social interaction, not only provide the involved neurons with instructive information needed to shape connection patterns to sustain adaptive function, but also exert a powerful influence on intrinsic and extrinsic growth-related mechanisms, so to create permissive conditions for neuritic remodeling. Here, we present an overview of recent findings concerning the effects of experience on molecular mechanisms underlying CNS structural plasticity, both in physiological conditions and after damage, with particular focus on activity-dependent modulation of growth-regulatory genes and epigenetic modifications.

Keywords: activity-dependent plasticity; enriched environment; epigenetics; experience; growth-regulatory cues; neuritic remodeling.

Figure 1

Modifications of chromatin structure in response to enriched environmental stimulation or injury in the mature CNS. On the left side of the figure, DNA methylation-dependent gene silencing is shown. Signaling pathways between neuronal activity and DNA methylation are still unclear. Methylation of specific sites in the genome recruits methyl-DNA binding proteins locally. All proteins that bind to methylated DNA also have a transcription-regulatory domain, which binds to adapter proteins, which in turn recruit histone deacetylases. Histone deacetylases alter chromatin structure through removal of acetyl groups (CH₃COO⁻) from histone core proteins (blue circles), leading to compaction of chromatin and transcriptional suppression. On the right side of the figure, the signaling pathway involving ERK, MSK, and CREB, implicated in the control of histone acetylation and chromatin structure, is shown. Phosphorylation and thus activation of CREB recruits CREB binding protein (CBP), which has histone acetyltransferase activity and leads to activation of gene transcription.

Figure 2

Possible mechanisms of action of enriched stimulation on structural plasticity. Enriched stimuli, which can comprise increased motor activity, sensory stimulation or social interaction, modulate the expression of several growth-regulatory cues, and alter chromatin structure, so to create permissive conditions for neuronal plasticity and behavioral adaptation. In addition, external stimulation provides the involved neurons with instructive information, needed to shape connections patterns able to sustain adaptive functions. BDNF, brain-derived neurotrophic factor; GAP-43, growth-associated protein-43; MMP, matrix metalloproteinase; tPA, tissue plasminogen activator; MAG, myelin-associated glycoprotein; CSPG, chondroitin sulfate proteoglycan.