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