Receptor trafficking and synaptic plasticity

Abstract

Synaptic plasticity is the basis of information storage in the brain. Two of the most studied forms of plasticity, long-term potentiation (LTP) and long-term depression (LTD), involve both glutamate and GABA (γ-aminobutyric acid) receptors, and it is becoming clear that the trafficking of these receptors is an important mechanism in both LTP and LTD. Postsynaptic changes in AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) are thought to be important for the expression of LTP. This could involve either the modulation of AMPARs at the synapse or the rapid recruitment of new AMPARs to the synapse. LTD might occur through a mirror mechanism or a distinct process. There is strong evidence that both LTP and LTD involve changes in the number of AMPARs at the synapse. AMPARs can enter or leave the synapse through exocytosis and endocytosis or through lateral diffusion within the membrane. Various protein kinases and phosphatases have been implicated in these processes. In addition, proteins that bind to AMPARs and regulate their function have also been identified. These include N-ethylmaleimide-sensitive factor (NSF) and the PDZ-domain-containing proteins postsynaptic density protein 95 (PSD-95), AMPAR-binding protein (ABP), glutamate-receptor interacting protein (GRIP) and protein interacting with C-kinase (PICK). NMDA (N-methyl-D-aspartate) receptors (NMDARs) are the most important known trigger for long-term synaptic plasticity. They also show considerable mobility within the membrane and between intracellular and extracellular compartments of cells, although these processes are less well understood than for AMPARs. There is evidence that such trafficking is regulated by activity and could be a mechanism for metaplasticity. Kainate receptors are also important for synaptic plasticity, but little is known about the regulation of their trafficking. Furthermore, the G-protein-coupled metabotropic glutamate receptors (mGluRs) bind to various proteins that could regulate their trafficking in response to activity. Ionotropic GABA_ARs help to regulate the activation of NMDARs, and transmission that is mediated by GABA_ARs is also modulated in response to activity. Their trafficking is likely to be important for synaptic plasticity, and this process shows some similarities to trafficking of AMPARs. Several proteins that bind GABA_ARs and could regulate their trafficking in response to activity have been identified. Metabotropic GABA_BRs are also important for plasticity, and several proteins have been identified that bind these receptors, but their functional importance is unclear. Some common principles are emerging in the regulation of receptor trafficking during synaptic plasticity. These include the stabilization of receptors at the membrane by scaffolding proteins and regulation by kinases and phosphatases. However, specific receptors or subunits are also trafficked by selective mechanisms.