Grant: Master's Award: Canada Graduate Research Scholarships - Master's program

Huntington's disease (HD) is caused by an expanded CAG repeat in the HTT gene, and growing evidence shows that ongoing somatic CAG expansion within vulnerable brain regions is a major driver of disease progression. HD brains also show early synaptic dysfunction, particularly hyperactivation of N-methyl-D-aspartate receptors (NMDARs). Under normal conditions, NMDARs support learning and memory by allowing controlled calcium entry, but in HD their hyperactivation leads to calcium overload, oxidative stress, and DNA double-strand breaks. Although small, transient breaks are part of normal gene regulation, persistent breaks is harmful and may further accelerate CAG expansion. A key unanswered question is whether NMDAR hyperactivation directly drives this expansion or whether these processes independently contribute to neuronal decline. We and others have shown that reducing the NMDAR subunit GluN3A safely normalizes NMDAR hyperactivation. GluN3A is normally expressed only during early development but becomes abnormally elevated in adult HD brains, making it a compelling therapeutic target. Using the R6/1 mouse model, we will test whether GluN3A-driven synaptic dysfuctions promotes DNA damage and accelerate CAG expansion in the hippocampus, a region critical for HD-related cognitive deficits. Mice will receive GluN3A knockdown or control treatment, followed by electrophysiology, high resolution imaging of DNA damage, and PCR-based CAG sizing. If our hypothesis is correct, GluN3A reduction will restore normal synaptic function, decrease DNA damage, and slow CAG expansion. This work will clarify whether early synaptic dysfunction directly shapes genomic instability in HD, with broad implications for therapeutic development across multiple repeat-expansion disorders.