Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Huntington disease is a lethal genetic disorder caused by inheritance of the mutated version of the huntingtin gene. Disease onset is defined by the appearance of motor symptoms, most noticeably chorea - sudden, uncontrollable movements - beginning usually in the mid-thirties to forties. Psychiatric symptoms, such as anxiety and depression, as well as deficits in learning and memory, may begin 15 years before overt disease onset, and are thought to be caused by malfunctioning connections between brain cells, also called synapses. If the amount of signaling through synapses is outside of a certain range brain activity will become unstable; processes known as homeostatic plasticity work to prevent this. This includes synaptic scaling, which adjusts the strength of synapses, and metaplasticity, which changes the likelihood of synapses' strength changing during learning. Since some proteins affected by Huntington disease are also involved in homeostatic plasticity, we suggest that the disease may impair these processes. We are testing this by growing brain cells from mice with and without the mutant huntingtin gene in dishes, treating them with drugs that increase or decrease their activity, and measuring their synaptic strength. We have found that cells which usually strengthen their synapses when their activity decreases do not do this when they have the mutant huntingtin gene, and are looking for the underlying reasons for this change. We will also test for similar changes in other cell types in slices of brain tissue. Finally, we will test whether a series of electric pulses which normally affect the ability of synapses to change their strength, work in slices of brain tissue from mice with the mutant gene. Understanding the biology underlying the early psychiatric and cognitive symptoms of Huntington disease will allow those affected to remain at work and independent longer instead of relying on a caregiver, improving their and their caregivers' quality of life.