Document Type

Article

Publication Date

6-1-2026

Comments

This article is the author's final published version in npj Parkinson's Disease, Volume 12, Issue 1, 2026, Article number 208.

The published version is available at https://doi.org/10.1038/s41531-026-01396-7. Copyright ©The Author(s) 2026.

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder marked by loss of substantia nigra dopaminergic neurons. Epidemiological evidence indicates that lifelong physical activity reduces both PD incidence and slows disease progression. Here, we examine how voluntary exercise induces long-lasting neuroprotection of the corticostriatal function in a murine model of α-synuclein–driven nigrostriatal pathology. In preformed fibril (PFF)-injected mice, long-lasting voluntary wheel running prevents degeneration of nigrostriatal dopaminergic terminals and improves motor performances. Intensive exercise normalizes spontaneous glutamatergic transmission and preserves corticostriatal long-term potentiation (LTP) in striatal spiny projection neurons. Exercise-induced LTP is dependent on activation of dopamine (DA) DA1, GluN2B-expressing NMDA and CB1 endocannabinoid (eCB) receptors. Pharmacological modulation of exercise-induced plasticity shows that, while in physiological conditions eCBs regulate synaptic depotentiation, persistence of LTP in active α-syn mice occurs independently of the eCB system, highlighting a critical interaction between DA and eCBs in long-term synaptic regulation. These findings identify voluntary exercise as a robust neuroprotective intervention with therapeutic relevance for early PD.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Language

English

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