Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype

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Abstract
Activity-dependent change in the efficacy of transmission is a basic feature of many excitatory synapses in the central nervous system. The best understood postsynaptic modification involves a change in responsiveness of AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor)-mediated currents following activation of NMDA ( N-methyl-D-aspartate) receptors1,2 or Ca 2+-permeable AMPARs3,4,5,6. This process is thought to involve alteration in the number and phosphorylation state of postsynaptic AMPARs2. Here we describe a new form of synaptic plasticity—a rapid and lasting change in the subunit composition and Ca2+ permeability of AMPARs at cerebellar stellate cell synapses following synaptic activity. AMPARs lacking the edited GluR2 subunit not only exhibit high Ca 2+ permeability7 but also are blocked by intracellular polyamines8,9,10,11. These properties have allowed us to follow directly the involvement of GluR2 subunits in synaptic transmission. Repetitive synaptic activation of Ca2+-permeable AMPARs causes a rapid reduction in Ca2+ permeability and a change in the amplitude of excitatory postsynaptic currents, owing to the incorporation of GluR2-containing AMPARs. Our experiments show that activity-induced Ca 2+ influx through GluR2-lacking AMPARs controls the targeting of GluR2-containing AMPARs, implying the presence of a self-regulating mechanism.