Clinical and preclinical studies have shown that intensive exercise enhances BDNF production with neuroprotective action in health and disease conditions. Here we test the hypothesis that intensive exercise prevents corticostriatal alterations caused by α-syn protofibrils (PFFs) spreading through the nigrostriatal system in an early models of Parkinson’s disease (PD). To test this hypothesis, rats received striatal bilateral injection with phosphate buffer or PFF to study the link between α-syn, synaptic NMDA receptors (NMDAR) retention, and BDNF signaling. Animals were divided into two groups, sedentary and active, respectively not subjected or subjected to physical activity for 4 weeks. All groups were tested for behavioral analyses, for molecular and electrophysiological experiments, and morphological investigations. At the end of the 4-week exposure to treadmill exercise, visuospatial learning and motor coordination as well as corticostriatal long-term potentiation (LTP) is restored only in PFF active group, but not in sedentary rats. The beneficial effects of exercise were associated with an increase in BDNF production, a preferential recruitment of GluN2B-expressing NMDAR during LTP induction, and a massive recovery of spiny projection neurons connectivity, with and a reduced α-syn spreading to the substantia nigra pars compacta. Pharmacological blockade of TrkB-R prevented the LTP exercise-dependent in the PFF active group, demonstrating an interaction of BDNF-TrkB complex with the GluN2B-NMDAR activated pathway in the rescue of striatal synaptic plasticity. Together, these results show that intensive physical exercise might be a valid non-pharmacological treatment for PD, useful to reduce disability and progression of motor symptoms caused by α-syn aggregates.