A schematic model of the molecular events contributing to the early and late phase of LTP in the Schaffer collateral pathway. A single train of action potentials initiates early LTP by activating NMDA receptors, leading to Ca2+ influx into the postsynaptic cell, and to the recruitment of a set of second messenger kinases including the calcium calmodulin-dependent protein kinase which phosphorylates existing AMPA receptors and also leads to the insertion of new receptors. There is also thought to be a retrograde signal that diffuses from the postsynaptic cell to the presynaptic terminals to enhance transmitter release. With four repeated trains, the Ca2+ influx also recruits adenylys cyclase, which activates the cAMP-dependent protein kinase (PKA) and MAPK. These kinases translocate to the nucleus where they phosphorylate CREB and other transciption factors. CREB in turn activates target genes that are thought to lead to structural changes. Mutations in mice that block PKA or CREB reduce the late phase of LTP and compromise long-term memory for space. The adenylyl cyclase can also by modulated by the modulatory transmitter dopamine acting through D1/D5 receptors.