Sex differences in behavior and striatal ascorbate release in the 140 CAG knock-in mouse model of Huntington's...

Ethological assessment of murine models of Huntington's disease (HD), an inherited neurodegenerative disorder, enables correlation between phenotype and pathophysiology. Currently, the most characterized model is the R6/2 line that develops a progressive behavioral and neurological phenotype by 6 weeks of age. A recently developed knock-in model with 140 CAG repeats (KI) exhibits a subtle phenotype with a longer progressive course, more typical of adult-onset HD in humans. We evaluated rotarod performance, open-field behavior, and motor activity across the diurnal cycle in KI mice during early to mid-adulthood. Although we did not observe any effects of age, relative to wild-type (WT) mice, KI mice showed significant deficits in both open-field climbing behavior and home-cage running wheel activity during the light phase of the diurnal cycle. An interesting sex difference also emerged. KI females spent more time in the open-field grooming and more time running during the diurnal dark phase than KI males and WT mice of both sexes. In striatum, the primary site of HD pathology, we measured behavior-related changes in extracellular ascorbate (AA), which is abnormally low in the R6/2 line, consistent with a loss of antioxidant protection in HD. KI males exhibited a 20-40% decrease in striatal AA from anesthesia baseline to behavioral activation that was not observed in other groups. Collectively, our results indicate behavioral deficits in KI mice that may be specific to the diurnal cycle. Furthermore, sex differences observed in behavior and striatal AA release suggest sex-dependent variation in the phenotype and neuropathology of HD.