Synaptic AMPA receptor composition in development, plasticity and disease

Key Points AMPA receptors (AMPARs) mediate nearly all fast excitatory neurotransmission in the mammalian CNS. AMPARs are heteromeric assemblies of four core subunits, GluA1–4, together with auxiliary subunits and a dynamically changing set of interacting proteins. The assembly and subunit composition of AMPARs undergo activity-dependent regulation during biogenesis. The presence or absence of the edited form of the GluA2 subunit, GluA2(R), determines whether the assembled AMPAR gates Ca 2+ . There is a wealth of evidence suggesting that the synaptic trafficking, retention and removal of AMPARs of specific subunit combinations and that have specific biophysical properties are of paramount importance for synaptic plasticity. These AMPAR-subtype-specific events are regulated both by protein interactions and by phosphorylation events within the carboxy-terminal tails. Recent studies reporting that the C-terminal tails are not essential for plasticity and that very few GluA1 subunits are phosphorylated have prompted a major re-evaluation of the fundamental mechanisms of AMPAR trafficking and synaptic plasticity. Understanding the molecular details of AMPAR assembly, trafficking, recycling and degradation, and how dysfunction affects synapses, neurons and networks will provide invaluable insights into neurological and neurodegenerative disease. AMPA receptor (AMPAR) subunit composition is thought to influence trafficking, but recent findings have challenged previously accepted models for how this might occur. In this Review, Henley and Wilkinson provide an overview of how different receptor subunits affect AMPAR assembly, trafficking and function under normal and pathological conditions. AMPA receptors (AMPARs) are assemblies of four core subunits, GluA1–4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs, and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity and in response to neuronal stress in disease. Recently, the subunit dependence of AMPAR trafficking has been questioned, leading to a reappraisal of this field. In this Review, we discuss what is known, uncertain, conjectured and unknown about the roles of the individual subunits, and how they affect AMPAR assembly, trafficking and function under both normal and pathological conditions.