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Title: Therapeutic potential of modulators of cannabinoid receptors in cerebellar ataxias
Author: Wang, Xiaowei
ISNI:       0000 0004 2716 6852
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2011
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Cerebellar ataxias (CAs) are a group of motor disorders associated with Purkinje cell (PC) degeneration for which no effective therapeutic treatment exists. Many studies have suggested that modulation of the body's endocannabinoid system may be of use in treatment of diseases involving changes to neuronal excitability. For example, hyperexcitability has been proposed as a mechanism underlying PC degeneration in CAs. In this thesis, electrophysiological, and also biochemical approaches have been used to investigate cannabinoid CBl receptor-mediated signalling in the cerebellum. This work was extended to an animal model of CA to investigate potential therapies; for example, exploiting exogenous cannabinoid effects as a putative means to modulate neuronal firing to protect against hyperexcitability-induced neuronal degeneration in the cerebellum. Intracellular patch-clamp recordings of mlPSCs at IN-PC synapses and extracellular multi- electrode array (MEA) recordings of spontaneous excitatory firing of PCs in the acute cerebellar slice preparation were combined. These studies demonstrated that the standard synthetic CBl receptor ligands (the agonist WIN55 and the antagonist AM251) modulate presynaptic GABA transmission at IN-PC synapses, which in turn affects PC output. Interestingly, results from C57BI/6 mice support the project's initial hypothesis by showing that exogenous CBl receptor antagonists act to increase GABA transmission at IN-PC synapses, which could protect against hyperexcitability-induced cerebellar PC degeneration and so offer therapeutic potential. This study also investigated the functional effects of another class of CBl ligand, the allosteric CBl receptor antagonist PSNCBAM1, for the first time. Whole-cell patch-clamp mlPSC recordings were used to demonstrate ligand- dependent effects of PSNCBAM-l at IN-PC synapses. Finally, work was extended to a pre- clinical animal model of CA, the ducky du2J mutant mouse strain which has deficits in the Ca2+ channel auxiliary u2o-2 subunit and which exhibits defective Ca2+ channel function. Electrophysiological recordings (patch-clamp & MEA) demonstrated that CBl receptor signalling was attenuated in +/du2J and du2J/du2J mice. Receptor binding methods (saturation and GTPyS binding assays) indicated that deficiency in CBl signalling may be due to attenuation of the intrinsic efficacy of CBl receptor ligands to activate G-protein in both du2J mutants, but not a gross reduction in CBl receptor expression. Results from du2J mutants suggest that Ca2+ channel defect ultimately causes impaired CBl receptor- mediated signalling in ataxic conditions. Not only is the attenuated CBl receptor-mediated signalling a novel finding, but it also prompts the important question 'is attenuated endocannabinergic signalling a common feature in human and mouse model ataxias?'
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available