Synapse-to-Nucleus ERK→CREB Transcriptional Signaling Requires Dendrite-to-Soma Ca²⁺Propagation Mediated by L-Type Voltage–Gated Ca²⁺Channels

The cAMP-response element-binding protein (CREB) transcription factor controls the expression of the neuronal immediate early genes c<i>-fos</i>, <i>Arc</i>, and <i>Bdnf</i> and is essential for long-lasting synaptic plasticity underlying learning and memory. Despite this critical role, there is still ongoing debate regarding the synaptic excitation-transcription (E-T) coupling mechanisms mediating CREB activation in the nucleus. Here we employed optical uncaging of glutamate to mimic synaptic excitation of distal dendrites in conjunction with simultaneous imaging of intracellular Ca²⁺ dynamics and transcriptional reporter gene expression to elucidate CREB E-T coupling mechanisms in hippocampal neurons cultured from both male and female rats. Using this approach, we found that CREB-dependent transcription was engaged following dendritic stimulation of <i>N</i>-methyl-d-aspartate receptors (NMDARs) only when Ca²⁺ signals propagated to the soma via subsequent activation of L-type voltage-gated Ca²⁺ channels resulting in activation of extracellular signal-regulated kinase MAP kinase signaling to sustain CREB phosphorylation in the nucleus. In contrast, dendrite-restricted Ca²⁺ signals generated by NMDARs failed to stimulate CREB-dependent transcription. Furthermore, Ca²⁺-CaM-dependent kinase-mediated signaling pathways that may transiently contribute to CREB phosphorylation following stimulation were ultimately dispensable for downstream CREB-dependent transcription and c-Fos induction. These findings emphasize the essential role that L-type Ca²⁺ channels play in rapidly relaying signals over long distances from synapses located on distal dendrites to the nucleus to control gene expression.