Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input

The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions. However, the precise mechanisms underlying this process remain unclear. One way to study action selection is to understand how it breaks down in pathological states. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinson’s disease therapy characterized by involuntary movements. We used an activity-dependent tool (FosTRAP) in conjunction with a mouse model of LID to investigate functionally distinct subsets of striatal direct pathway medium spiny neurons (dMSNs). In vivo, levodopa differentially activates dyskinesia-associated (TRAPed) dMSNs compared to other dMSNs. We found this differential activation of TRAPed dMSNs is likely to be driven by higher dopamine receptor expression, dopamine-dependent excitability, and excitatory input from the motor cortex and thalamus. Together, these findings suggest how the intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection. [Display omitted] •FosTRAP captures striatal neurons activated in levodopa-induced dyskinesia•Levodopa evokes high firing rates in TRAPed direct pathway striatal neurons (dMSNs)•TRAPed dMSNs show enhanced dopamine sensitivity and excitatory synaptic input Ryan et al. explore the cellular and synaptic mechanisms of levodopa-induced dyskinesia, a complication of Parkinson’s disease treatment. Using an activity-dependent mouse line to capture dyskinesia-associated neurons, they find a subset of striatal direct pathway neurons with high levodopa-evoked activity and enhanced dopamine signaling and excitatory synaptic input.