Gene Regulation by Nuclear Calcium and Its Antagonism by NMDAR/TRPM4 Signaling

Synaptic activity-driven gene expression is essential for a long list of neuroadaptations at nearly all levels of nervous system organization and function, influencing the structure of individual neurons and synapses, altering their circuit connectivity, and ultimately resulting in changes in behavior. Accordingly, activity-regulated genomic responses control fundamental adaptive processes in neurons such as memory formation and the acquisition of resistance to excitotoxicity and neurodegeneration. Activity-regulated transcription can also, however, mediate persistent maladaptations such as addiction and chronic pain. Synaptic activity initiates the signaling cascades that regulate transcription in neurons by transient increases in the intracellular levels—and particularly in the nuclear levels—of the ubiquitous second messenger calcium. In this review, we provide a comprehensive overview of the mechanisms underlying the generation of these calcium responses and the signaling pathways they regulate. Additionally, we highlight extrasynaptic N-methyl-D-aspartate (NMDA) receptor activity as a common pathomechanism that suppresses synaptic activity-driven, calcium signaling-regulated gene expression in neurodegenerative diseases.