Parkinson’s disease (PD) is a chronic, neurodegenerative disease that affects one percent of the population over the age of sixty. To our knowledge, there is no therapy that can slow the progression of the disease. Deep brain stimulation (DBS) of either the subthalamic nucleus (STN) or the globus pallidus interna (GPi) is well established to provide significant therapeutic efficacy in alleviating the motor symptoms of PD, yet our understanding of effects on disease progression remains limited. Previous studies have shown that long-term, high-frequency stimulation of the STN halts degeneration of the substantia nigra induced by intrastriatal 6-hydroxydopamine (6-OHDA) injections and significantly increases brain-derived neurotrophic factor (BDNF) in the nigrostriatal system, primary motor cortex and entopeduncular nucleus (EP). These results suggest that STN DBS can induce plasticity within basal ganglia circuitry and has the potential to provide neuroprotection in PD.In order to examine the role of BDNF in the neuroprotective effects of STN DBS, I examined in our 6-OHDA rat model if blockade of the trophic receptor for BDNF, tropomyosin-related kinase type 2 (trkB), would alter the afforded protection. I also examined the effect of trkB antagonism on the recovery of motor function provided by STN DBS for unilaterally lesioned rats. Beyond elucidation of the mechanism for STN DBS-mediated neuroprotection, I evaluated if STN DBS would similarly facilitate nigral neuroprotection against α-synuclein overexpression-mediated toxicity. Lastly, I evaluated if DBS of the EP, the homologous structure of the GPi in the rat, would result in similar results as STN stimulation, namely alleviation of a unilateral motor deficit, nigral neuroprotection and increased BDNF. The data demonstrate that BDNF plays a critical role in the neuroprotective effects of STN DBS and in the alleviation of a unilateral motor deficit. The data also show that STN DBS is unable to provide neuroprotection against α-synuclein overexpression-mediated insult, but I call into question the usefulness of this model for the question of if STN DBS is disease modifying. I also present data that support abandoning EP DBS in the rat as an appropriate model of GPi DBS for PD. I conclude with remarks on the implications of this work for the clinic, including the use of a common variant in the gene for BDNF as a biomarker that may allow the development of ‘precision medicine’ approaches for the refinement of current medical practice guidelines for PD.
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