Aberrant chloride homeostasis and inhibitory synaptic transmission in Huntington's disease

Huntingtonâ s disease (HD) is primarily characterized by progressive motor incoordination and involuntary movements that result from neurodegeneration of the striatum. However, cognitive impairments and learning and memory deficits involving the hippocampus emerge in the early stages of the disease and precede the motor impairments by ~15 years. Despite the critical role of GABAergic inhibition in learning and memory, inhibition has not been studied in detail in the HD hippocampi. In my PhD thesis, I have presented three novel pieces of evidence that collectively demonstrate the causative role of Cl- homeostasis in hippocampal-related learning and memory deficits in HD mice. First, the reduced expression of the Cl--extruding cotransporter KCC2, and the increased expression in the Cl--importing cotransporter NKCC1 together result in excitatory GABAergic transmission in the hippocampi of the R6/2 transgenic mouse model of HD. Second, inhibition of the Cl--importing transporter NKCC1 with the FDA-approved drug bumetanide restores hyperpolarizing GABAergic inhibition and rescues the performance of R6/2 mice on hippocampal-associated behavioral tests. Third, the strength of overall hippocampal inhibition is altered at both the presymptomatic and symptomatic stages of the disease, and involves the disruption of both presynaptic and postsynaptic components. Taken together, my PhD work not only significantly increases our understanding of a less recognized aspect of HD, but also for the first time describes the involvement of Cl- homeostasis in a neurodegenerative disease.Ph.D.2020-03-26 00:00:0