UCSF

The basal ganglia are a series of interconnected subcortical nuclei involved in movement, action selection, and decision making. These processes are dependent on the coordinated output of the striatal direct and indirect pathways, which is dysregulated in neurological conditions such as Parkinson’s disease, Huntington’s Disease, and forms of dystonia. However, the specific cells, circuits, and patterns of activity within the brain that contribute to disease manifestations, such as involuntary movements, or dyskinesias, are not well understood. To address this gap, we have used two mouse models of human dyskinesias, paroxysmal nonkinesigenic dyskinesia (PNKD) and levodopa-induced dyskinesia (LID), to investigate whether aberrant striatal activity is a root cause of dyskinesia. Using a variety of in vivo and ex vivo techniques to both record and manipulate neural activity, we found that abnormal patterns of activity in the striatum give rise to dyskinesia. Interestingly, in PNKD we see profound reductions in striatal indirect pathway activity during dyskinesia, whereas in LID there are decreases in indirect pathway activity, but also abnormally high direct pathway activity during dyskinesia. Further, we found that the decrease in indirect pathway activity is necessary and sufficient for drug-induced dyskinesia in PNKD, while an increase in activity in a subset of direct pathway neurons is necessary and sufficient for drug-induced dyskinesia in LID. In both models, we found evidence of aberrant striatal synaptic plasticity as a cellular correlate of dyskinesia: depressed excitatory input onto indirect pathway neurons in the case of PNKD, and enhanced excitatory input onto direct pathway neurons in LID. While these results are largely in support of the classical model of basal ganglia function, we also found heterogeneity within the canonical direct pathway in LID, and identified a subclass of direct pathway neurons with exceptionally high levodopa-evoked firing that correlates strongly with dyskinesia, Importantly, these results may guide the development of new therapeutics for hyperkinetic disorders based on targeting specific subclasses of striatal neurons or their connections.