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

The cAMP-response element-binding protein (CREB) transcription factor controls the expression of the neuronal immediate early genes c, , and 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 Ca 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 -methyl-d-aspartate receptors (NMDARs) only when Ca signals propagated to the soma via subsequent activation of L-type voltage-gated Ca channels resulting in activation of extracellular signal-regulated kinase MAP kinase signaling to sustain CREB phosphorylation in the nucleus. In contrast, dendrite-restricted Ca signals generated by NMDARs failed to stimulate CREB-dependent transcription. Furthermore, Ca-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 Ca channels play in rapidly relaying signals over long distances from synapses located on distal dendrites to the nucleus to control gene expression.