Subthalamic nucleus deep brain stimulation is neuroprotective in the A53T α-synuclein Parkinson's disease rat model

Abstract

Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective symptomatic therapy for motor deficits in Parkinson's disease (PD). An additional, disease-modifying effect has been suspected from studies in toxin-based PD animal models, but these models do not reflect the molecular pathology and progressive nature of PD that would be required to evaluate a disease-modifying action. Defining a disease-modifying effect could radically change the way in which DBS is used in PD. Methods: We applied STN-DBS in an adeno-associated virus (AAV) 1/2-driven human mutated A53T α-synuclein (aSyn)-overexpressing PD rat model (AAV1/2-A53T-aSyn). Rats were injected unilaterally, in the substantia nigra (SN), with AAV1/2-A53T-aSyn or control vector. Three weeks later, after behavioral and nigrostriatal dopaminergic deficits had developed, rats underwent STN-DBS electrode implantation ipsilateral to the vector-injected SN. Stimulation lasted for 3 weeks. Control groups remained OFF stimulation. Animals were sacrificed at 6 weeks. Results: Motor performance in the single pellet reaching task was impaired in the AAV1/2-A53T-aSyn–injected stim-OFF group, 6 weeks after AAV1/2-A53T-aSyn injection, compared to preoperative levels (–82%; p < 0.01). Deficits were reversed in AAV1/2-A53T-aSyn, stim-ON rats after 3 weeks of active stimulation, compared to the AAV1/2-A53T-aSyn stim-OFF rats (an increase of ∼400%; p < 0.05), demonstrating a beneficial effect of DBS. This motor improvement was maintained when the stimulation was turned off and was accompanied by a higher number of tyrosine hydroxylase+ SN neurons (increase of ∼29%), compared to AAV1/2-A53T-aSyn stim-OFF rats (p < 0.05). Interpretation: Our data support the putative neuroprotective and disease-modifying effect of STN-DBS in a mechanistically relevant model of PD. Ann Neurol 2017;81:825–836.