Diametric neural ensemble dynamics in parkinsonian and dyskinetic states

By Jones G. Parker, Jesse D. Marshall, Biafra O. Ahanonu, Yu-Wei Wu, Tony Hyun Kim, Benjamin F. Grewe, Yanping Zhang, Jin Zhong Li, Jun B. Ding, Michael D. Ehlers and 1 more. Nature, 2018

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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. In mouse models of Parkinson’s disease and dyskinesia, striatal spiny projection neurons of the direct and indirect pathways have abnormal, imbalanced levels of spontaneous and locomotor-related activity, with the two different disease states characterized by opposite abnormalities.

View Paper: https://www.semanticscholar.org/paper/c654f91cd429a58cca5dfdb3aa2a99ee9df32740

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Citations in the corpus

Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats (2024, background): “Levodopa remains the standard treatment for early-stage PD (Parker et al., 2018; Lofredi et al., 2021), but long-term levodopa administration can lead to the development of levodopa-induced dyskinesia (LID), a severe complication that commonly affects advanced PD patients and severely impacts their…”