Ca2+ influx through the NMDA receptor initiates subsequent molecular pathways that have a defined role in establishing long-lasting synaptic changes. The molecular signaling initiated by a rise in Ca2+ within the spine leads to phosphorylation of Cyclic AMP Response Element binding protein (CREB1) at serine S133, leading to transcription of genes involved in long lasting changes at the synapse. The phosphorylation of CREB1 triggered by increased Ca2+ can be brought about by distinct molecular pathways that may involve MAP kinase, activation of adenylate cyclase and activation of CaMKIV (reviewed by Cohen and Greenberg 2008 and Hunt and Castillo 2012).