RyR-mediated Ca ²⁺ release elicited by neuronal activity induces nuclear Ca ²⁺ signals, CREB phosphorylation, and Npas4/RyR2 expression

Abstract

The expression of several hippocampal genes implicated in learning and memory processes requires that Ca ²⁺ signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca ²⁺ in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca ²⁺ signals to the nucleus. Here, we present evidence showing that Ca ²⁺ release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca ²⁺ signals induced by gabazine (GBZ) addition, glutamate uncaging in the dendrites, or high-frequency field stimulation of primary hippocampal neurons. Additionally, GBZ treatment significantly increased cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation—a key event in synaptic plasticity and hippocampal memory—and enhanced the expression of Neuronal Per Arnt Sim domain protein 4 (Npas4) and RyR2, two central regulators of these processes. Suppression of RyR-mediated Ca ²⁺ release with ryanodine significantly reduced the increase in CREB phosphorylation and the enhanced Npas4 and RyR2 expression induced by GBZ. We propose that RyR-mediated Ca ²⁺ release induced by neuronal activity, through its contribution to the sequential generation of nuclear Ca ²⁺ signals, CREB phosphorylation, Npas4, and RyR2 up-regulation, plays a central role in hippocampal synaptic plasticity and memory processes.