Regulation of calcium-permeable AMPA receptors at cerebellar interneuron synapses

Fast excitatory synaptic transmission in the central nervous system is mediated principally by glutamate, acting on AMPA receptors (AMPARs). The functional properties of these receptors reflect their subunit composition (GluR1-4) and dictate key features of the excitatory postsynaptic current, and thus the transmission process. Importantly, insertion or removal of AMPARs at the synapse underlies the expression of certain well-characterised forms of long-term synaptic plasticity. Recently, several additional forms of plasticity have been shown to involve the specific regulation of Ca2+-permeable (GluR2-lacking) AMPARs. At parallel fibre synapses onto cerebellar stellate cells, Ca2+ influx through AMPARs triggers an autoregulatory change in their subunit composition. In this thesis I have investigated factors that may trigger or influence this type of subunit change. I discovered that a switch in AMPAR subtype (from Ca2+-permeable to mainly Ca2+-iimpermeable AMPARs) occurs during development of stellate cells. This change is accompanied by a decrease in synaptic channel conductance. Activation of either mGluRs or GABABRs also results in switch in AMPAR subtype - a selective loss of synaptic Ca2+-permeable AMPARs, triggered by a rise in intracellular Ca2+. My experiments also reveal that both types of metabotropic receptor are tonically active, and therefore constitutively regulate subunit-specific synaptic targeting of AMPARs. My results identify a signalling mechanism likely to drive the dynamic switch in AMPAR Ca2+-permeability, and demonstrate that AMPAR subunit composition can be modified by postsynaptic actions of GABA, as well as glutamate.