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

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 (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor)-mediated currents following activation of NMDA (N-methyl-D-aspartate) receptors(1,2) or Ca(2+)-permeable AMPARs(3-6). This process is thought to involve alteration in the number and phosphorylation state of postsynaptic AMPARs(2). Here we describe a new form of synaptic plasticity-a rapid and lasting change in the subunit composition and Ca(2+) permeability of AMPARs at cerebellar stellate cell synapses following synaptic activity. AMPARs lacking the edited GluR2 subunit not only exhibit high Ca(2+) permeability(7) but also are blocked by intracellular polyamines(8-11). These properties have allowed us to follow directly the involvement of GluR2 subunits in synaptic transmission. Repetitive synaptic activation of Ca(2+)-permeable AMPARs causes a rapid reduction in Ca(2+) 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.