Needham, EL; (2012) AMPA receptors and auxiliary subunits in central synaptic transmission. Doctoral thesis , UCL (University College London).

Abstract

AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the central nervous system (CNS). AMPARs are tetrameric assemblies of AMPAR subunits forming a functional ion channel gated by the binding of glutamate. The functional properties of AMPARs dictate key features of the excitatory postsynaptic current and they differ with receptor subunit composition (GluA1-4). The incorporation of GluA2 determines many key properties of AMPARs including their permeability to calcium. GluA2-lacking AMPARs are calcium permeable and their expression is tightly regulated. Transmembrane AMPAR regulatory proteins (TARPs) also play a vital role in the regulation of AMPAR properties. TARPs aid the trafficking of AMPARs to the neuronal surface and their synaptic targeting. They also regulate AMPAR channel properties and their gating. AMPARs are known to be dynamic at the neuronal surface. AMPAR density at the synapse changes with synaptic strength, as does their subunit composition. These regulated changes modify the AMPAR-mediated postsynaptic response. While these changes in synaptic AMPARs and synaptic strength are vital for functions such as learning and memory, the altered regulation of AMPARs is implicated in many pathophysiological states including many neurodegenerative diseases. By investigating the properties of AMPARs in central synaptic transmission, and in recombinant expression systems, I have examined the role of AMPARs in a specific disease, the expression of calcium-permeable AMPARs, and the role of TARPs in regulating AMPAR properties. The aim of this thesis was to investigate the function of AMPARs at intact synapses formed in vivo and in recombinant expression systems. My experiments have shown that excitatory and inhibitory synaptic transmission are both altered in the cerebellum of a mouse model of the most common progressive neurodegenerative disease of childhood, Batten disease. I have also shown that spinal motor neurons express a mixture of calcium permeable- and calcium impermeable AMPARs at the synapse. Additionally, my results suggest that the prototypical TARP, stargazin, appears to regulate a proportion of these AMPARs. Finally, I have considered the role of a protein related to the TARP family, γ-6, in the regulation of recombinant AMPAR properties. γ-6 was found to regulate AMPAR trafficking and pharmacology, but is unable to modify single-channel conductance.

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