UCSF

Abnormal involuntary movements, or dyskinesias, are seen in many neurologic diseases, including disorders where the brain appears grossly normal. This observation suggests that alterations in neural activity or connectivity may underlie dyskinesias. One influential model proposes that involuntary movements are driven by an imbalance in the activity of striatal direct and indirect pathway neurons (dMSNs and iMSNs, respectively). Indeed, in some animal models, there is evidence that dMSN hyperactivity contributes to dyskinesia. Given the many diseases associated with dyskinesia, it is unclear whether these findings generalize to all forms. Here, we used male and female mice in a mouse model of paroxysmal nonkinesigenic dyskinesia (PNKD) to assess whether involuntary movements are related to aberrant activity in the striatal direct and indirect pathways. In this model, as in the human disorder PNKD, animals experience dyskinetic attacks in response to caffeine or alcohol. Using optically identified striatal single-unit recordings in freely moving PNKD mice, we found a loss of iMSN firing during dyskinesia bouts. Further, chemogenetic inhibition of iMSNs triggered dyskinetic episodes in PNKD mice. Finally, we found that these decreases in iMSN firing are likely because of aberrant endocannabinoid-mediated suppression of glutamatergic inputs. These data show that striatal iMSN dysfunction contributes to the etiology of dyskinesia in PNKD, and suggest that indirect pathway hypoactivity may be a key mechanism for the generation of involuntary movements in other disorders.SIGNIFICANCE STATEMENT Involuntary movements, or dyskinesias, are part of many inherited and acquired neurologic syndromes. There are few effective treatments, most of which have significant side effects. Better understanding of which cells and patterns of activity cause dyskinetic movements might inform the development of new neuromodulatory treatments. In this study, we used a mouse model of an inherited human form of paroxysmal dyskinesia in combination with cell type-specific tools to monitor and manipulate striatal activity. We were able to narrow in on a specific group of neurons that causes dyskinesia in this model, and found alterations in a well-known form of plasticity in this cell type, endocannabinoid-dependent synaptic LTD. These findings point to new areas for therapeutic development.