A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia

• Published in: Neuron (Cambridge, Mass.) Vol. 97; no. 4; pp. 787 - 795.e6
• Main Authors: Girasole, Allison E., Lum, Matthew Y., Nathaniel, Diane, Bair-Marshall, Chloe J., Guenthner, Casey J., Luo, Liqun, Kreitzer, Anatol C., Nelson, Alexandra B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-02-2018; Elsevier Limited
• Subjects: Animals; Antiparkinson Agents - administration & dosage; Basal ganglia; Behavior; Brain; Central nervous system diseases; Corpus Striatum - drug effects; Corpus Striatum - physiopathology; direct pathway; Disease Models, Animal; Dopamine; Dyskinesia; Dyskinesia, Drug-Induced - physiopathology; Female; Gene expression; Genetics; Information processing; Levodopa; Levodopa - administration & dosage; levodopa-induced dyskinesia; Male; Mesencephalon; Mice, Inbred C57BL; Mice, Transgenic; Motor Cortex - drug effects; Motor Cortex - physiopathology; Movement disorders; Neostriatum; Neural Pathways - drug effects; Neural Pathways - physiopathology; Neurons; Neurons - drug effects; Neurons - physiology; Optics; Optogenetics; Parkinson Disease - physiopathology; Parkinson's disease; Recombination; Rodents; Sensorimotor system; Basal ganglia; levodopa-induced dyskinesia; direct pathway; dopamine; Parkinson’s disease; optogenetics
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.01.017

Parkinson’s disease is characterized by the progressive loss of midbrain dopamine neurons. Dopamine replacement therapy with levodopa alleviates parkinsonian motor symptoms but is complicated by the development of involuntary movements, termed levodopa-induced dyskinesia (LID). Aberrant activity in the striatum has been hypothesized to cause LID. Here, to establish a direct link between striatal activity and dyskinesia, we combine optogenetics and a method to manipulate dyskinesia-associated neurons, targeted recombination in active populations (TRAP). We find that TRAPed cells are a stable subset of sensorimotor striatal neurons, predominantly from the direct pathway, and that reactivation of TRAPed striatal neurons causes dyskinesia in the absence of levodopa. Inhibition of TRAPed cells, but not a nonspecific subset of direct pathway neurons, ameliorates LID. These results establish that a distinct subset of striatal neurons is causally involved in LID and indicate that successful therapeutic strategies for treating LID may require targeting functionally selective neuronal subtypes.
•FosTRAP captures neurons activated in levodopa-induced dyskinesia (LID) brain-wide•Primarily striatal direct pathway neurons (dMSNs) are activated during dyskinesia•Reactivation of TRAPed striatal neurons produces dyskinesia in the absence of levodopa•Inhibition of TRAPed striatal neurons, but not nonspecific dMSNs, reduces LID
Girasole et al. use the FosTRAP system to capture and manipulate populations associated with levodopa-induced dyskinesia (LID) brain-wide. They show that a subset of striatal neurons is necessary and sufficient in the production of LID.