Exercise promotes glutamate transporter-mediated glutamate uptake in the striatum to regulate MSN plasticity and alleviate behavioral and functional impairments in PD rats.

This study investigated whether exercise ameliorates behavioral deficits in a rat model of Parkinson's disease (PD) by regulating medium spiny neuron (MSN) plasticity via striatal astrocytic excitatory amino acid transporters (EAATs). The PD model was induced by 6-hydroxydopamine (6-OHDA) and confirmed by apomorphine rotation. Exercised rats underwent 4 weeks of treadmill training. We assessed motor function using beam walking and cylinder tests. Striatal pathology was evaluated via tyrosine hydroxylase (TH) immunohistochemistry, glutamate (Glu) enzyme-linked immunosorbent assay, c-Fos tracing, Western blotting for Glutamate-aspartate transporter (GLAST)/ Glu transporter-1 (GLT-1)/N-methyl-D-aspartate receptor (NMDAR), Golgi staining for dendritic spines, and in vivo local field potential (LFP) recording. Compared to controls, PD rats exhibited motor impairment, dopamine depletion, increased striatal Glu levels, NMDAR expression, and β-oscillations, alongside reduced EAAT expression and spine density. Exercise significantly reversed these abnormalities and improved behavior. Notably, pharmacological blockade of EAATs in exercised rats completely abolished these neuroprotective effects, reinstating the PD phenotype. These findings indicate that treadmill exercise upregulates striatal EAATs (GLAST/GLT-1), enhances Glu uptake, reduces extracellular Glu, and suppresses NMDAR overactivation and β-oscillations. This restoration of Glu homeostasis promotes MSN morphological and functional remodeling, serving as a critical mechanism for exercise-induced behavioral improvement in PD.