Melissa Solem

Huntington’s disease (HD) is a neurodegenerative disease resulting in devastating motor, cognitive, and psychiatric deficits. HD is caused by a poly-glutamine expansion of exon 1 of the Htt gene resulting in misfolding and aggregation of the mutant HTT protein (mHTT). The striatum, a brain region involved in motor control, is the region most significantly impacted in HD and is the focus of most HD studies. However, despite well-documented deficits in learning and memory in HD, knowledge of the potential implication of the hippocampus remains limited due to the lack of hippocampal pathology observed in various models of HD. We now report enhanced hippocampal mHTT aggregation by modifying the commonly used knock-in HD model zQ175, which expresses a human exon 1 of Htt containing ~188 CAG repeats under the endogenous mouse Htt promoter. We show that after removing a PGK-Neomycin cassette expressed in zQ175 mice using the Cre recombinase system, the newly generated zQ175∆Neo mice exhibit significantly enhanced mHTT aggregation in the hippocampus, a region with very limited mHTT aggregation in the original zQ175 model. Importantly, zQ175∆Neo mice also exhibit enhanced mHTT aggregation in the striatum and increased neuropathology shown by decreased expression of striatal neuron markers compared to zQ175. Intriguingly, despite increased mHTT aggregation in the hippocampus, minimal markers of hippocampal pathology were observed through analyses investigating neuroinflammation, cortical layer thinning, chaperone expression, and synaptic density. Our findings imply that hippocampal neurons are resilient to mHTT toxicity therefore suggesting that cognitive deficits in HD might not be caused by hippocampal degeneration. Our data further demonstrates the selective vulnerability of striatal neurons in HD and suggests that the zQ175∆Neo mouse model may serve as a valuable tool to understand the fundamental susceptibility differences to mHTT toxicity between different neuronal subtypes.