When Action Selection Fails: Aberrant Striatal Direct Pathway Activity in Parkinson's Disease and Dyskinesia
Action selection relies on the coordinated activity of striatal direct and indirect pathway medium spiny neurons (dMSNs and iMSNs, respectively). Loss of dopamine in Parkinson's disease is thought to disrupt this balance. While dopamine replacement with levodopa may restore normal function, the development of involuntary movements (levodopainduced dyskinesia [LID]) limits therapy. We have investigated how chronic dopamine loss and replacement with levodopa modulate the firing of identified MSNs in behaving animals. Using a variety of transgenic mouse tools, optogenetics, and electrophysiology, we find that dMSNs show profoundly reduced firing in the parkinsonian state, while iMSNs show elevated firing during immobility. While levodopa treatment evokes the predicted bidirectional changes in firing rate in dMSNs and iMSNs, we also found a subpopulation of dMSNs with abnormally high levodopa-evoked firing rates, which correlate specifically with dyskinesia. Using an activity-dependent approach, we have been able to show that these neurons participate in the causal circuitry of dyskinesia, and may have unique synaptic and intrinsic properties. These findings provide key insights into the circuit mechanisms underlying parkinsonism and LID, with implications for developing targeted therapies.