Pearce, Sarah Elizabeth; (2018) The role of auxiliary subunits in AMPA receptor function. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glutamate receptors of the AMPA-subtype mediate the majority of fast excitatory neurotransmission in the central nervous system (CNS). These receptors are associated with auxiliary proteins that have been shown to affect AMPA receptor (AMPAR) properties. Transmembrane AMPAR Regulatory Proteins (TARPs) were the first identified AMPAR auxiliary subunits, and since then, further auxiliary subunits continue to be identified. In this thesis, I investigate the effects of a novel auxiliary protein candidate – FRRS1L – on AMPAR function, as well as the involvement of TARPs in mediating AMPAR plasticity in a model of ischaemic stroke. I show that when co-expressed with both homomeric GluA1 and heteromeric GluA1/GluA2 AMPAR subunits in tsA201 cells, FRRS1L slows recovery from receptor desensitization, without significant effect on other AMPAR properties. When the prototypical TARP stargazin is additionally co-expressed, the effect of FRRS1L is lost and the receptor properties appear as if only stargazin were associated. I examine the endogenous expression of FRRS1L in the CNS, and find that it is highly abundant in multiple brain regions including the hippocampus, cortex and cerebellum. In cultured hippocampal neurons, overexpressed FRRS1L does not influence mEPSC amplitude or frequency. In a model of ischaemic stroke, direct ASIC1-a activation through lowering of the pH (acidosis) is sufficient to drive AMPAR plasticity in cultured hippocampal neurons. This manifests as a decrease in the GluA2 subunit, resulting in an increase of CP-AMPARs in the membrane. I show that this change in AMPAR subunit expression following acidosis is likely accompanied by an increase in TARP γ-8 expression. Using various techniques, I explore the change in CPAMPAR expression and cell excitability. I show that following acidosis, there is an increase in Ca2+ entry into the cells, which is likely mediated through CPAMPARs.

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