4 Year MRC PhD Programme: α5-GABAA receptor modulators for the treatment of cognitive impairment associated with Huntington’s disease.

Huntington’s disease (HD) is a genetic disorder with offspring having a 50% chance of inheriting the fatal gene. It generally strikes by middle-age, causing neurodegeneration and motor-dysfunction. However, 10-15 years prior many patients experience cognitive impairment that greatly impacts on their life. We use a mouse model carrying the mutant HD gene. Like humans, we find these mice present with cognitive impairments, long before motor dysfunction. Additionally, they exhibit a deficit in a form of synaptic plasticity (LTP) in their hippocampus, a region associated with learning/ memory. Importantly, we have discovered that the HD hippocampus over-expresses a subtype of inhibitory GABAA receptor (α5-GABAAR) and that acute administration of α5IA, a specific α5-GABAAR antagonist, rescues both the cognitive and synaptic plasticity deficit (2). We are involved in a Wellcome Trust- funded programme to develop such drugs as a treatment for this devastating disorder. Your proposed project is multidisciplinary. The study will utilise electrophysiological-behavioural analysis and computational methodology to investigate the role of α5-GABAARs in hippocampal signalling, how this function is perturbed in the HD mouse and how α5-GABAAR antagonists modify brain-activity. You will be trained in electrophysiological analysis of control and HD mouse hippocampal brain slices (JL), behavioural investigation of their cognitive function (RL) and in an exciting new development, we can now record hippocampal/cortical activity in mice performing cognitive tasks (RL,SM). The latter technique results in large data files, which will be analysed using novel computational methods of data analysis in Matlab (DS,SM,RL). This is a highly translational research proposal. Whilst this project focuses on cognition/HD, the approach can be used for other neurological/psychiatric diseases, facilitating direct tests of treatment hypotheses, leading to novel therapeutics.