Aerobic Exercise Improves Motor Performance by Reducing Total ERK Expression and Hyperexcitability of Striatal D2-MSNs in MPTP-Induced Parkinsonian Mice.

Aerobic exercise improves motor dysfunction in Parkinson's disease (PD), but the striatal cell-type-specific mechanisms underlying this effect remain incompletely understood. Here, we investigated whether altered total extracellular signal-regulated kinase (ERK) expression and Mapk1/3-associated functional changes in dorsolateral striatal dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) are associated with exercise-related functional recovery in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice. Mice underwent four weeks of moderate-intensity treadmill training, followed by behavioral assessment, tyrosine hydroxylase (TH) immunohistochemistry, ERK/PENK immunofluorescence, D2-Cre/DIO-shRNA-mediated Mapk1/3 knockdown, qRT-PCR, and whole-cell patch-clamp recordings. Compared with control mice, MPTP-treated mice showed reduced locomotor activity, shortened stride length, fewer TH-positive neurons in the substantia nigra pars compacta, increased total ERK/PENK double-positive cells in the dorsolateral striatum, and enhanced D2-MSN excitability and excitatory synaptic input. Compared with sedentary MPTP-treated mice, exercise improved open-field and gait performance, increased TH-positive neuronal counts, reduced ERK/PENK double-positive cells, and attenuated D2-MSN hyperexcitability and excessive spontaneous excitatory postsynaptic current frequency and amplitude. Cell-type-targeted Mapk1/3 knockdown reduced Mapk1 and Mapk3 mRNA expression and produced behavioral, histological, molecular, and electrophysiological effects similar to exercise. Combining Mapk1/3 knockdown with exercise did not further enhance these outcomes relative to exercise with scramble control, supporting a non-additive pattern consistent with overlapping Mapk1/3-associated functional mechanisms. Honokiol-based pharmacological perturbation provided additional supportive functional evidence, although these findings were interpreted cautiously because honokiol is pharmacologically pleiotropic and cannot be used to infer ERK activation. Together, these results suggest that modulation of total ERK expression and Mapk1/3-associated functional abnormalities in dorsolateral striatal D2-MSNs may contribute to exercise-associated motor improvement in MPTP-induced parkinsonian mice.