Field, Martin; (2019) GABAA receptor desensitization shapes the kinetics and plasticity of inhibitory neurotransmission. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

GABAA receptors are anion-permeable pentameric ligand-gated ion channels. They are the primary mediators of inhibitory neurotransmission in the central nervous system. As with many other ion channels, they are known to desensitize. This is a process involving the entry into a long-lived closed state after exposure to agonist. Although studies of receptors in recombinant systems and structural work have provided a lot of information about the entry of the receptor into the desensitized state, its physiological role remains unclear. In this project I sought to further elucidate the physiological role of entry of GABAA receptors into the desensitized state using mutations in the desensitization gate previously identified by our laboratory. I initially studied these mutations in recombinant expression systems to further characterise their effects on GABAA receptor kinetics and thus demonstrated that desensitization indeed effects the kinetics of phasic- and tonic-like responses. I then confirmed these phenotypes in cultured hippocampal neurons. Treatments of neurons with GABA and allosteric modulators of GABAARs were then used in combination with the desensitization mutants to assess whether desensitization has any long-term effects on inhibitory synapses. GABAAR desensitization was found to result in a PKC-dependent long-term potentiation of inhibitory synapses.

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