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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:639540 |
| Date | January 2007 |
| Creators | Kelly, L. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1444768/ |
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