Grant: CIHR Fellowship

Background: Huntington disease (HD) is a devastating neurodegenerative disorder characterized by cognitive, psychiatric and motor symptoms that generally appear in adulthood. HD is caused by a mutation in the gene encoding the huntingtin (Htt) protein and virtually all HD patients express some degree of both the mutated and non-mutated protein. While promising therapeutic strategies involve lowering the amount of Htt, the non-mutated Htt protein may play a key role in nervous system function and it is proving difficult to specifically reduce only the mutated form of the protein. We have preliminary data to suggest that reducing Htt expression may have serious side-effects on brain cell function in key areas that are also affected in HD. Aims: Here, I propose to conduct the first thorough exploration of the consequences of reducing Htt at the cellular and synaptic level. Specifically, I will use different concentrations of antisense oligonucleotides to reduce Htt levels to varying degrees in the mouse brain as well as in cultured mouse neurons. I will then use electrophysiological recordings to screen for any effects Htt reduction may have on basic cell membrane properties, synaptic neurotransmitter release as well as synaptic plasticity, the neural mechanism underlying learning and memory. HD is associated with a well-established collection of cellular and synaptic deficits, so it is also of interest to determine whether specific mHtt reduction is more effective than general Htt reduction at restoring the cellular and synaptic function in a mouse model of HD. This will be achieved by using an ASO that can specifically reduce mutant Htt in this particular mouse model and compare the results to an ASO that reduces both mutant and non-mutant Htt. Significance: A thorough screen of the possible side-effects of general Htt reduction is absolutely essential for the field of HD research and will provide clinically-relevant data regardless of the outcome.