Protective mechanisms induced by STN deep brain stimulation in A53T alpha-synuclein Parkinson’s disease rodent models

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, accompanied by multiple non-motor and motor symptoms. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a surgical treatment used to reduce motor impairments when pharmacological therapy is no longer effective. However, neither the mechanisms triggering motor deficits in PD nor the therapeutic effect of STN-DBS are fully understood. Recently, pathological accumulations of the plasticity-associated receptor TrkB, essential for motor learning and modulation, were observed in striatal neurons of PD patients. In this study, TrkB clusters were analyzed in detail in a progressive PD rat model. Results showed a dependency of TrkB cluster formations on dopaminergic input fibers and indicated a denervation level required to develop these aggregates. However, STN-DBS reduced the number of TrkB clusters to a level similar to healthy controls by preserving upstream dopaminergic projections, essential for the intact TrkB translocation mechanism. To further advance reverse translational DBS research, a standardized wireless DBS system for mice was developed to address the problem of custom-made wireless DBS devices, which hampered reproducibility. This commercially available stimulation system was characterized by lightweight, long-term power supply and programmability. In addition, a step-by-step implantation protocol was developed. The application in hemiparkinsonian mice demonstrated the feasibility in small rodents and the precise implantation technique by targeting the STN. The improved motor performance of stimulated PD mice was captured by a novel deep learning-based gait analysis, the Parkinson’s disease severity score for mice. This behavioral test combined multiple PD-related gait features and evaluated the severity of motor impairment. The results of this experiment contribute to the understanding of PD-associated mechanisms in the cortico-basal ganglia-circuit. In addition, this reverse translational study demonstrates cellular modifications induced by STN-DBS and might contribute to optimizing the intervention in PD patients by indicating that an early application can be even more effective. Finally, the new DBS device for mice enriches the methodological scope of DBS animal research. The novel gait analysis as a sensitive behavioral assessment may reduce the number of animals required for such an experiment.