Diametric neural ensemble dynamics in parkinsonian and dyskinetic states

Jones G. Parker, Jesse D. Marshall, Biafra Ahanonu, Yu-Wei Wu, Tony Hyun Kim, Benjamin F. Grewe, Yanping Zhang, Jin Zhong Li, Jun B. Ding, Michael D. Ehlers () and Mark J. Schnitzer ()
Additional contact information
Jones G. Parker: Stanford University
Jesse D. Marshall: Stanford University
Biafra Ahanonu: Stanford University
Yu-Wei Wu: Stanford University School of Medicine
Tony Hyun Kim: Stanford University
Benjamin F. Grewe: Stanford University
Yanping Zhang: Stanford University
Jin Zhong Li: Stanford University
Jun B. Ding: Stanford University School of Medicine
Michael D. Ehlers: Pfizer Inc.
Mark J. Schnitzer: Stanford University

Nature, 2018, vol. 557, issue 7704, 177-182

Abstract: Abstract Loss of dopamine in Parkinson's disease is hypothesized to impede movement by inducing hypo- and hyperactivity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively. The opposite imbalance might underlie hyperkinetic abnormalities, such as dyskinesia caused by treatment of Parkinson’s disease with the dopamine precursor l-DOPA. Here we monitored thousands of SPNs in behaving mice, before and after dopamine depletion and during l-DOPA-induced dyskinesia. Normally, intermingled clusters of dSPNs and iSPNs coactivated before movement. Dopamine depletion unbalanced SPN activity rates and disrupted the movement-encoding iSPN clusters. Matching their clinical efficacy, l-DOPA or agonism of the D2 dopamine receptor reversed these abnormalities more effectively than agonism of the D1 dopamine receptor. The opposite pathophysiology arose in l-DOPA-induced dyskinesia, during which iSPNs showed hypoactivity and dSPNs showed unclustered hyperactivity. Therefore, both the spatiotemporal profiles and rates of SPN activity appear crucial to striatal function, and next-generation treatments for basal ganglia disorders should target both facets of striatal activity.

Date: 2018
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DOI: 10.1038/s41586-018-0090-6

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