Figure 5.

Signaling pathways in the spine. (A) Schematic diagram of major signaling enzymes that mediate changes in synaptic plasticity driven by calcium influx through activated NMDARs. Critical early targets of CaMKII include AMPARs, TARPs, and SynGAP. RasGRF can activate both Ras and Rac. The critical targets of calcineurin are not known. One possibility is the cofilin phosphatase Slingshot, which dephosphorylates and activates the F-actin regulator cofilin. Calcium/CaM-dependent AC and cAMP-phosphodiesterase (PDE) are both present in spines; their responses to calcium could generate a transient spike in cAMP, activating Epac. Ras and Rap regulate trafficking of AMPARs, but their downstream targets, beyond the MAPKs, are not yet known. RasGRF and Ras, acting through the GTPase exchange factor TIAM1 can activate Rac, which regulates pathways that control polymerization of actin. TrkB receptors that respond to the central nervous system (CNS) hormone brain-derived neural factor (BDNF) can provide tonic activation of Ras and Rap. (B) Synaptic regulation of AMPAR trafficking. A critical step in the induction of LTP is the trapping of additional AMPARs in the PSD scaffold through association of TARP and PSD95, which is increased by phosphorylation of residues on TARP by CaMKII. Dephosphorylation of these residues by PP1 can produce loss of AMPARs and depotentiation. Calcineurin, a calcium/CaM-dependent phosphatase, regulates PP1 and endocytosis. Addition of AMPARs to the dendritic plasma membrane by exocytosis, and their removal by endocytosis, occurs at perisynaptic sites in the spine and along the dendritic shaft. Changes in the activity of Ras and Rap are regulated by downstream targets of calcium/CaM, including RasGRF, SynGAP, and adenylyl cyclase (AC). Active Ras and Rap, in turn, activate the MAPKs ERK1/2 and p38. Pathways downstream from ERK facilitate exocytosis, whereas those downstream from p38 facilitate endocytosis. Many of the intermediate steps in the processes downstream from MAPKs are unknown.