Increased AMPAR function is observed after exposure to psychostimulants, which can significantly modulate reward-directed behavior. Synapses can be strengthened or weakened in response to changing neuronal activity, a mechanism that is thought to underlie learning and memory. Following induction of long-term potentiation (LTP), synaptic strengthening can be achieved through active insertion of GluA2-lacking AMPARs (i.e., GluA1/A1 or GluA1A/3 receptors). Compared with GluA2-containing AMPARs, GluA2-lacking AMPARs have greater channel conductance and, which are calcium permeable and can trigger calcium-dependent signaling cascades (Figure 2A) (Kauer and Malenka, 2007). Conversely, long-term depression (LTD) is associated with removal of AMPARs from synapses (Malinow and Malenka, 2002); thus, AMPAR trafficking is a powerful and rapid mechanism by which synapses can be strengthened and weakened to affect behavior. Furthermore, changes in phosphorylation state or splice variants can also regulate AMPAR-mediated synaptic transmission (Braithwaite et al., 2000; Kessels and Malinow, 2009; Wang et al., 2005). In general, GluA1 phosphorylation increases AMPAR currents (Derkach et al., 1999; Roche et al., 1996) and can also drive insertion of AMPARs into synapses (Esteban et al., 2003), which can strengthen synapses and lead to LTP.
