A dystonia mouse model with motor and sequencing deficits paralleling human disease.

Abstract

The dystonias are a group of movement disorders characterized by involuntary twisting movements and postures. A lack of well characterized behavioral models of dystonia has impeded identification of circuit abnormalities giving rise to the disease. Most mouse behavioral assays are implemented independently of cortex, but cortical dysfunction is implicated in human dystonia. It is therefore important to identify dystonia models in which motor cortex-dependent behaviors are altered in ways relevant to human disease. The goal of this study was to characterize a cortically-dependent behavior in the recently-developed Dlx-CKO mouse model of DYT1 dystonia. Mice performed two tasks: skilled reaching and water-elicited grooming. These tests assess motor learning, dexterous skill, and innate motor sequencing. Furthermore, skilled reaching depends strongly on motor cortex, while dorsal striatum is critical for normal grooming. Dlx-CKO mice exhibited significantly lower success rates and pellet contacts compared to control mice during skilled reaching. Despite the skilled reaching impairments, Dlx-CKO mice adapt their reaching strategies. With training, they more consistently contacted the target. Grooming patterns of Dlx-CKO mice are more disorganized than in control mice, as evidenced by a higher proportion of non-chain grooming. However, when Dlx-CKO mice engage in syntactic chains, they execute them similarly to control mice. These abnormalities may provide targets for preclinical intervention trials, as well as facilitate determination of the physiologic path from torsinA dysfunction to motor phenotype.