Excessive Firing of Dyskinesia-Associated Striatal Direct Pathway Neurons is Gated By Dopamine and Excitatory Synaptic Input

Abstract

The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions, but the precise mechanisms remain unclear. One way to study action selection is when it breaks down. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinsons 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. This activation is likely to be driven by two cellular mechanisms we identified through ex vivo electrophysiology: higher sensitivity to dopamine and stronger excitatory input from the motor cortex and thalamus. Together, these findings suggest how intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.