Striatal activation by optogenetics induces dyskinesias in the 6‐hydroxydopamine rat model of Parkinson disease

• Published in: Movement disorders Vol. 32; no. 4; pp. 530 - 537
• Main Authors: F. Hernández, Ledia, Castela, Ivan, Ruiz‐DeDiego, Irene, Obeso, Jose A., Moratalla, Rosario
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2017
• Subjects: 6-Hydroxydopamine; Adrenergic Agents - toxicity; Animals; Antiparkinson Agents - adverse effects; Brain - metabolism; Channelrhodopsins; Corpus Striatum - metabolism; Dihydroxyphenylalanine; Disease Models, Animal; Dopamine; Dynorphins - metabolism; dyskinesias; Dyskinesias - etiology; Forebrain; FosB protein; Functional Laterality; Genetics; Information processing; Levodopa; Levodopa - adverse effects; l‐dopa; Male; Medial forebrain bundle; medium spiny neurons; Movement disorders; Neostriatum; Neurodegenerative diseases; Optics; optogenetics; Optogenetics - adverse effects; Oxidopamine - toxicity; Parkinson disease; Parkinson Disease - etiology; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Parkinson's disease; Proto-Oncogene Proteins c-fos - metabolism; Rats; Rats, Sprague-Dawley; Rodents; Spiny neurons; Substantia nigra; Transduction, Genetic; Tyrosine 3-Monooxygenase - metabolism; Parkinson disease; medium spiny neurons; l-dopa; dyskinesias; optogenetics
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.26947

ABSTRACT Background: Long‐term levodopa (l‐dopa) treatment is associated with the development of l‐dopa–induced dyskinesias in the majority of patients with Parkinson disease (PD). The etiopathogonesis and mechanisms underlying l‐dopa–induced dyskinesias are not well understood. Methods: We used striatal optogenetic stimulation to induce dyskinesias in a hemiparkinsonian model of PD in rats. Striatal dopamine depletion was induced unilaterally by 6‐hydroxydopamine injection into the medial forebrain bundle. For the optogenetic manipulation, we injected adeno‐associated virus particles expressing channelrhodopsin to stimulate striatal medium spiny neurons with a laser source. Results: Simultaneous optical activation of medium spiny neurons of the direct and indirect striatal pathways in the 6‐hydroxydopamine lesion but l‐dopa naïve rats induced involuntary movements similar to l‐dopa–induced dyskinesias, labeled here as optodyskinesias. Noticeably, optodyskinesias were facilitated by l‐dopa in animals that did not respond initially to the laser stimulation. In general, optodyskinesias lasted while the laser stimulus was applied, but in some instances remained ongoing for a few seconds after the laser was off. Postmortem tissue analysis revealed increased FosB expression, a molecular marker of l‐dopa–induced dyskinesias, primarily in medium spiny neurons of the direct pathway in the dopamine‐depleted hemisphere. Conclusion: Selective optogenetic activation of the dorsolateral striatum elicits dyskinesias in the 6‐hydroxydopamine rat model of PD. This effect was associated with a preferential activation of the direct striato‐nigral pathway. These results potentially open new avenues in the understanding of mechanisms involved in l‐dopa–induced dyskinesias. © 2017 International Parkinson and Movement Disorder Society