RyR-mediated Ca²⁺ release elicited by neuronal activity induces nuclear Ca²⁺ signals, CREB phosphorylation, and...

The expression of several hippocampal genes implicated in learning and memory processes requires that Ca²⁺ signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca²⁺ in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca²⁺ signals to the nucleus. Here, we present evidence showing that Ca²⁺ release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ release induced by neuronal activity, through its contribution to the sequential generation of nuclear Ca²⁺ signals, CREB phosphorylation, Npas4, and RyR2 up-regulation, plays a central role in hippocampal synaptic plasticity and memory processes.