Restoring Compromised Cl^- in D2 Neurons of a Huntington's Disease Mouse Model Rescues Motor Disability

Huntington's disease (HD) is a progressive neurodegenerative disorder with no cure, characterized by significant neurodegeneration of striatal GABAergic medium spiny neurons (MSNs). Early stages of the disease are characterized by the loss of dopamine 2 receptor-expressing MSNs (D2 MSNs) followed by degeneration of dopamine 1 receptor-expressing MSNs (D1 MSNs), leading to aberrant basal ganglia signaling. While the early degeneration of D2 MSNs and impaired GABAergic transmission are well-documented, potassium chloride cotransporter 2 (KCC2), a key regulator of intracellular chloride (Cl^-), and therefore GABAergic signaling, has not been characterized in D1 and D2 MSNs in HD. We aimed to investigate whether Cl^- regulation was differentially altered in D1 and D2 MSNs and may contribute to the early degeneration of D2 MSNs in male and female symptomatic R6/2 mice. We used electrophysiology to record the reversal potential for GABA_A receptors (E _GABA), a read-out for the efficacy of Cl^- regulation, in striatal D1 and D2 MSNs and their corresponding output structures. During the early symptomatic phase (P55-P65), Cl^- impairments were observed in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl^- regulation was also dysfunctional in the globus pallidus externa, resulting in GABA-mediated excitation. When we overexpressed KCC2 in D2 MSNs using AAV-mediated delivery, we delayed the onset of motor impairments in R6/2 mice. We demonstrate that Cl^- homeostasis is differentially altered in D1 and D2 MSNs and may contribute to the enhanced susceptibility of D2 MSNs during HD progression.