ABHD6 Inhibition Rescues a Sex-Dependent Deficit in Motor Coordination in The HdhQ200/200 Mouse Model of Huntington's Disease.

Abstract

Huntington's Disease is associated with motor behavior deficits that are lessened by few therapeutic options. This preliminary study tested if pharmacological inhibition of α/β-hydrolase domain containing 6 (ABHD6), a multifunctional enzyme expressed in the striatum, rescues behavioral deficits in HdhQ200/200 mice. Previous work has shown that this model exhibits a reduction in spontaneous locomotion and motor coordination at 8 and 10 months of age, with a more severe phenotype in female mice. Semi-quantitative immunohistochemistry analysis indicated no change in striatal ABHD6 expression at 8 months of age, but a 40% reduction by 10 months in female HdhQ200/200 mice compared to female wild-type (WT) littermates. At 8 months of age, acute ABHD6 inhibition rescued motor coordination deficits in female HdhQ200/200 mice without affecting WT performance. ABHD6 inhibition did not impact spontaneous locomotion, grip strength, or overall weight in either group, showing that effects were specific to motor coordination. At 10 months of age, semi-chronic ABHD6 inhibition by osmotic pump delivery also rescued motor coordination deficits in female HdhQ200/200 mice without affecting female WT littermates. Our preliminary study suggests that ABHD6 inhibition improves motor performance in female HdhQ200/200 mice.