Activity-Dependent NPAS4 Expression and the Regulation of Gene Programs Underlying Plasticity in the Central Nervous System

Figure 2

The process of plasticity reactivation in the adult visual system. The reinstatement of plasticity caused by FLX in adult life is associated with signal transduction pathways that involve the activation of long-distance serotonergic transmission, a downregulation of local intracortical inhibitory circuitries and enhanced NPAS4 expression. The experimental evidence is consistent with a model in which the increased serotonergic signaling shifts the inhibitory/excitatory balance, thus activating intracellular mechanisms that eventually promote epigenetic modifications of chromatin structure that, in turn, allow for the expression of plasticity genes in adult life, among which NPAS4 plays a key role. NPAS4 seems to turn on a transcriptional program that underlies structural and functional plasticity while facilitating, in parallel or in series, a reorganization of inhibitory circuitries that might contribute to the homeostasis of cortical excitability by driving inhibition during this phase of enhanced plasticity. The transitory expression of NPAS4 target genes may ultimately set in motion downstream physiological mechanisms that provide a permissive environment for changes in adult visual cortical circuitries (e.g., enhanced Bdnf-trkB signaling, removal of extracellular matrix components that are inhibitory for plasticity, and enhanced dendritic spines density and remodeling). Continuous arrows represent established interactions between molecular and cellular processes mentioned (boxes). Dashed lines represent interactions that remain to be ascertained. Reproduced from [101] with permission.