CREB PHOSPHORYLATION AND DEPHOSPHORYLATION - A CA2(- AND STIMULUS DURATION-DEPENDENT SWITCH FOR HIPPOCAMPAL GENE-EXPRESSION())

While changes in gene expression are critical for many brain functions , including long-term memory, little is known about the cellular proce sses that mediate stimulus-transcription coupling at central synapses. In studying the signaling pathways by which synaptic inputs control t he phosphorylation state of cyclic AMP-responsive element binding prot ein (CREB) and determine expression of CRE-regulated genes, we found t wo important Ca2+/calmodulin (CaM)-regulated mechanisms in hippocampal neurons: a CaM kinase cascade involving nuclear CaMKIV and a calcineu rin-dependent regulation of nuclear protein phosphatase 1 activity. Pr olongation of the synaptic input on the time scale of minutes, in part by an activity-induced inactivation of calcineurin, greatly extends t he period over which phospho-CREB levels are elevated, thus affecting induction of downstream genes.