Dystonia is a neurological
movement disorder characterized by sustained or intermittent muscle contractions, repetitive movement, and sometimes abnormal postures.
DYT1 dystonia is one of the most common genetic dystonias, and most patients carry heterozygous
DYT1 ∆GAG mutations causing a loss of a
glutamic acid of the
protein torsinA. Patients can be treated with
anticholinergics, such as
trihexyphenidyl, suggesting an abnormal
cholinergic state. Early work on the cell-autonomous effects of
Dyt1 deletion with ChI-specific
Dyt1 conditional knockout mice (
Dyt1 Ch1KO) revealed abnormal electrophysiological responses of striatal ChIs to
muscarine and
quinpirole, motor deficits, and no changes in the number or size of the ChIs. However, the Chat-cre line that was used to derive
Dyt1 Ch1KO mice contained a
neomycin cassette and was reported to have ectopic cre-mediated recombination. In this study, we generated a
Dyt1 Ch2KO mouse line by removing the
neomycin cassette in
Dyt1 Ch1KO mice. The
Dyt1 Ch2KO mice showed abnormal paw clenching behavior, motor coordination and balance deficits, impaired motor learning, reduced striatal
choline acetyltransferase protein level, and a reduced number of striatal ChIs. Furthermore, the mutant striatal ChIs had a normal
muscarinic inhibitory function, impaired
quinpirole-mediated inhibition, and altered current density. Our findings demonstrate a cell-autonomous effect of
Dyt1 deletion on the striatal ChIs and a critical role for the striatal ChIs and corticostriatal pathway in the pathogenesis of
DYT1 dystonia.