Huntington’s disease (HD) is a genetic disorder with offspring having a 50% chance of inheriting the fatal gene. Classical symptoms usually appear at middle-age, indicating neurodegeneration and motor-dysfunction. However, 10-15 years prior many patients experience cognitive impairment that greatly impacts their quality of life and that of their families and carers (1). We use a mouse model carrying the mutant HD gene to study this process. Like humans, we find these mice present with cognitive impairments in various behavioural tasks 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 aims to study the interactions between different brain regions affected in HD (hippocampus, prefrontal cortex, entorhinal cortex, striatum) to identify the neural networks underlying cognitive symptoms and how these may be influenced by α5-GABAA receptors (3). The study will utilise in vivo electrophysiology in awake, behaving mice alongside ex vivo LTP studies to investigate how the function of α5-GABAARs is perturbed in the HD mouse and how α5-GABAAR modulators modify brain activity. You will be trained in recording and analysing electrophysiological and behavioural data and use MatLab to design an analysis pipeline to investigate the interactions of brain rhythms from different regions. Network activity such as theta-gamma coupling, considered to underlie memory formation, will be recorded in the HD mouse for the first time in this novel project. These phenomena are emerging as biomarkers in other neurological conditions, such as Alzheimer’s disease, but such recordings in HD are novel, This is a highly translational research proposal- whilst this project focuses on cognition/HD, the approach can be used for other neurological/psychiatric disorders, facilitating direct tests of treatment hypotheses, leading to novel therapeutics.
2) Mohler, H., Rudolph, U. (2017). Disinhibition, an emerging pharmacology of learning and memory. F1000 Research 101: 1-10.
3) Keeley, S., et al (2017) Modelling fast and slow gamma oscillations with interneurons of different subtype. J Neurophysiol 117(3):950-965.