| Summary: | AMPA receptors (AMPARs) mediate majority of excitatory synaptic transmission, and are involved in fast neuronal glial signaling in the central nervous system (CNS). These receptors are tetrameric assemblies that function as homomeric or heteromeric combinations of four AMPAR subunits (GluA1-4). Many key AMPAR properties are determined by the GluA2 subunit, the absence of which renders the AMPAR calcium permeable. Calcium permeable AMPARs (CP-AMPARs) are relatively widespread in the CNS being present in certain neurons and many glia. The calcium permeability of neuronal AMPARs is known to be relatively plastic, changing during development and following high frequency synaptic activity. It is clear that calcium permeable AMPARs play an important role in normal functions of Bergmann glia and oligodendrocyte precursor cells, however factors that regulate the CP-AMPAR in glial cells are still poorly understood. Little is known about the transmembrane auxiliary AMPA subunit (TARPs) present in glial cells. In Chapter 3 of this thesis, I consider the role of transmembrane AMPAR regulatory proteins (TARPs) in controlling AMPAR channel properties and trafficking. In particular, these experiments identify γ-5 as a novel TARP that occurs mainly in glial cells, and is present at high levels in Bergmann glia. Functionally, this TARP appears selective for long form AMPAR subunits (predominantly calcium permeable). My experiments also demonstrate that γ-5 co-localizes with a late endosome protein. Uniquely, γ-5 appears selective for the trafficking of GluA2, and is dependent on the protein SAP97 for trafficking and/or localisation. Oligodendrocyte precursor cells (OPCs), which are responsible for the formation of myelinating cells in the CNS, form a large proportion of the glial cells present in developing brain. OPCs are vulnerable to cell death in conditions such as periventricular white matter damage (hypoxic-ischemic white matter injury) in newborns. In Chapter 4, I have investigated factors that regulate calcium permeable AMPARs in OPCs, including mGluRs and purinergic receptors. Surprisingly I find that these receptors regulate calcium permeable AMPARs. This chapter identifies key mechanisms underlying this switch in AMPAR subtype, including the TARP γ-2 (Stargazin) that is involved in mGluR-induced ‘plasticity’ of AMPARs in OPCs. The experiments described in the final chapter, investigates the transmembrane AMPAR regulatory protein cornichon-3 (CNIH3). In this thesis I identified that the AMPAR regulatory protein cornichon-3 (CNIH3) is expressed at the cell surface in OPCs and that when over-expressed can influence their AMPAR channel properties.
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