Validation of a torsinA cerebellar knockdown model of DYT1 dystonia

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. DYT1 dystonia is an early-onset dystonia caused by DYT1/TOR1A gene mutations with reduced penetrance. It is believed that dystonia is produced by abnormal brain networks, but details remain unknown. Recent studies have shown that acute cerebellar knockdown of torsinA using small hairpin RNAs (shRNAs) can induce overt dystonia in adult mice. However, shRNAs have off-target effects that may alter the expression of unintended genes. To avoid this issue, we generated an alternate acute torsinA knockdown model using cre-loxP technology by injecting AAV- cre into the cerebellum of the Dyt1 loxP/loxP mouse. These knockdown mice exhibited overt dystonia and displayed a spinning behavior, characterized by bidirectional circling or spinning during tail suspension. The overt dystonia and spin behavior were not observed in control mice injected with the AAV-GFP virus. Additionally, the knockdown mice showed decreased spontaneous firing and reduced intrinsic excitability of Purkinje cells. These findings confirmed that the acute cerebellar knockdown of torsinA can produce overt dystonia and further support the cerebellum’s role in the pathogenesis of DYT1 dystonia. However, the emergence of a spinning phenotype raises questions about the validity of the acute knockdown models as accurate representations of human dystonia.