Synaptic mGluR activation drives plasticity of calcium-permeable AMPA receptors

In contrast with conventional NMDA receptor-dependent synaptic plasticity, the synaptic events controlling the plasticity of GluR2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) remain unclear. At parallel fiber synapses onto cerebellar stellate cells, Ca2+ influx through AMPARs triggers a switch in AMPAR subunit composition, resulting in loss of Ca2+ permeabilty. Paradoxically, synaptically induced depolarization will suppress this Ca2+ entry by promoting polyamine block of CP-AMPARs. We therefore examined other mechanisms that may control this receptor regulation under physiological conditions. We found that activation of both mGluRs and CP-AMPARs is necessary and sufficient to drive an AMPAR subunit switch and that by enhancing mGluR activity, GABA(B)R activation promotes this plasticity. Furthermore, we found that mGluRs and GABA(B)Rs are tonically activated, thus setting the basal tone for EPSC amplitude and rectification. Regulation by both excitatory and inhibitory inputs provides an unexpected mechanism that determines the potential of these synapses to show dynamic changes in AMPAR Ca2+ permeability.