Regulation of AMPA receptor trafficking and synaptic plasticity
Highlights
► Highly dynamic trafficking of AMPARs regulates synaptic strength and plasticity. ► Subunit-specific AMPAR interacting proteins regulate receptor trafficking. ► Genetic deletion of AMPAR interacting proteins impairs synaptic plasticity, learning, and memory.
Introduction
The mammalian central nervous system comprises the incredibly complex connectivity between billions of neurons that are highly specialized for the fast processing and transmission of cellular signals. Communication between neurons, each of which contains thousands of synapses, underlies all basic and higher-order information processing essential for normal brain function. The ability of neural circuits to strengthen or weaken their connectivity forms a molecular basis underlying the experience-dependent changes in adaptive behaviors.
Synaptic plasticity can be regulated at the presynaptic side by altering the efficacy of neurotransmitter release, or on the postsynaptic side by changing the density, types, and properties of neurotransmitter receptors. AMPA receptors (AMPARs) are the principal ionotropic glutamate receptors that mediate fast excitatory synaptic transmission in mammalian brain. AMPARs are tetrameric assemblies of highly homologous subunits encoded by four different genes, GluA1-4. The trafficking of AMPARs into and out of synapses is highly dynamic and is regulated by subunit-specific AMPAR interacting proteins as well as by various post-translational modifications that occur on their cytoplasmic carboxyl terminal (C-terminal) domains. The regulated trafficking of AMPARs is a major mechanism underlying activity-induced changes in synaptic transmission. In general, increases in AMPAR function at synapses result in the long-term potentiation (LTP) of synaptic strength, whereas removal of synaptic AMPARs leads to long-term depression (LTD) [1]. This review focuses on recent advances providing new insights into the molecular control of AMPAR trafficking by proteins that directly interact with the intracellular domains of GluA1 and GluA2.
Section snippets
AMPAR structure and subunit composition
All AMPAR subunits consist of highly homologous extracellular and transmembrane regions, but vary in their intracellular C-terminal domains. The GluA1, GluA4, and an alternatively spliced form of GluA2 (GluA2L) contains long C-terminal domains, whereas the GluA2, GluA3, and an alternatively spliced form of GluA4 (GluA4S) have shorter C-terminal domains (Figure 1). Expression of these subunits is developmentally regulated and is region-specific. The C-termini of AMPAR subunits contains multiple
AMPA receptor trafficking
The number of AMPARs at synapses is dependent on relative rates of exocytosis and endocytosis at the postsynaptic membrane. Enhanced receptor exocytosis and recycling occur during synaptic potentiation, while increased rate of endocytosis results in LTD [1, 4]. The delivery of AMPARs to the synapse requires dynein-dependent or kinesin-dependent transport of AMPARs-containing vesicles (or endosomes) and SNARE-mediated fusion events at the plasma membrane. Recent studies have identified myosinVa
AMPA receptor interacting proteins
As mentioned above, subunit composition of AMPARs determine the routes of AMPAR trafficking, such that GluA1 is dominant over GluA2 during activity-dependent AMPAR exocytosis, while GluA2 is the primary determinant during endocytosis and postendocytic endosomal sorting [1]. This differential regulation is mainly due to interactions of intracellular C-terminal domain of GluA subunits with various components of the PSD and their associated proteins that function during receptor internalization
Concluding remarks
Cumulative evidence over the past two decades has placed AMPAR trafficking as a major regulatory mechanism in controlling synaptic plasticity, learning, and memory. The past few years have seen a rapid progress in the field revealing the complexity of AMPAR trafficking pathways (Figure 2). More importantly, the molecular details regulating AMPAR endosomal trafficking and sorting have started to be elucidated through identification of new AMPAR interacting proteins and study of genetically
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We apologize to those authors whose work was not cited due to space restrictions. Work in our laboratory is supported by grants from the National Institute of Health and the Howard Hughes Medical Institute (to R.L.H.). V.A. is supported by fellowships from the International Human Frontier Science Program (LT00399/2008-L) and the Australian National Health and Medical Research Council (ID: 477108).
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