AMPA Receptor Trafficking and the Control of Synaptic Transmission

meable to calcium and that controls synaptic plasticity. Activation of NMDA receptors leads to the appearance of functional AMPA receptors (“unsilencing”) in previously silent synapses, thereby potentiating synaptic transmission (Malenka and Nicoll, 1999; Malinow et al., Morgan Sheng1,2 and Sang Hyoung Lee2 Department of Neurobiology and Howard Hughes Medical Institute Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114 2000). This postsynaptic potentiation could be due to the activation of nonfunctional AMPA receptors already existing in synapses (e.g., by phosphorylation), or by the delivery of new AMPA receptors to the postsynaptic Glutamate is the major excitatory neurotransmitter in membrane. Supporting the latter idea, the level of AMPA mammalian brain. After release from the presynaptic receptors in synapses is influenced by synaptic activity terminal, glutamate acts on specific receptors that are and varies greatly between different synapses, with clustered in the postsynaptic membrane. The AMPAsome synapses being devoid of AMPA receptors (Nustype glutamate receptor, a ligand-gated cation channel ser, 2000). that opens upon glutamate binding, mediates most of AMPA Receptor Delivery the excitatory (depolarizing) postsynaptic response in Recent studies have revealed that AMPA receptors can glutamatergic synapses. Thus, changing the activity of translocate from nonsynaptic to synaptic sites, providAMPA receptors is a powerful way to control the ing a cell biological basis for controlling the synaptic strength of synaptic transmission, which is important level of AMPA receptors and hence postsynaptic refor information storage in the brain. sponsiveness (Lüscher et al., 2000; Malinow et al., 2000). AMPA receptors are formed from heteromeric (probaThe first direct evidence for movement of AMPA recepbly tetrameric) combinations of subunits GluR1-4. GluR tors came when Shi et al. (1999) showed that following subunits can be divided into two groups, GluR1 and strong synaptic stimulation and NMDA receptor activaGluR4, and GluR2 and GluR3, based on sequence simition, GFP-tagged GluR1 translocated from the main larity of their C-terminal cytoplasmic domains. In the shaft of dendrites into spines, specialized dendritic prohippocampus, GluR2 and GluR3 have short cytoplasmic trusions on which excitatory synapses are formed. tails of around 50 amino acids with a conserved C-terminal sequence (-SVKI) that binds to cytoplasmic PDZ proteins GRIP/ABP and PICK-1 (Sheng and Pak, 2000; Scannevin and Huganir, 2000). The longer GluR1 cytoplasmic tail (terminating in -ATGL) binds to a distinct set of proteins (Figure 1). In the hippocampus (part of the brain important for learning and memory and where many experiments on synaptic transmission are conducted), endogenous AMPA receptors are composed mainly of GluR1/GluR2 and GluR2/GluR3 heteromers (Wenthold et al., 1996). Recent work from Roberto Malinow and colleagues, culminating in a paper in Cell (Shi et al., 2001), has defined an important set of subunitspecific rules governing the delivery of AMPA receptors to synapses. These rules provide new insights into the postsynaptic trafficking of AMPA receptors and open inroads into the molecular mechanisms that tune synaptic strength. Silent Synapses A simple way to modify synaptic responses is to change the number of postsynaptic AMPA receptors available for activation by released glutamate. Electrophysiological and morphological evidence for such a mechanism has accumulated over the past few years, driven by the discovery of ‘‘silent synapses.’’ A subset of glutamatergic synapses in many parts of the CNS lack AMPA receptor currents. These so-called “silent synapses” nevertheless contain functional NMDA receptors, another type of ionotropic glutamate receptor that is perFigure 1. Membrane Topology and Cytoplasmic Protein Interactions of AMPA Receptor Subunits