Diametric neural ensemble dynamics in parkinsonian and dyskinetic states

Jones Griffith 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*, Mark J. Schnitzer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)177-182
Number of pages6
JournalNature
Volume557
Issue number7704
DOIs
StatePublished - May 10 2018

ASJC Scopus subject areas

  • General

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