BJRP 011002

Perturbations of corticostriatal activity in α-synecluin mammalian models of Parkinson’s disease: treatment by dorsal column stimulation

Abstract

In Parkinson’s disease (PD), the progressive degeneration of a selective population of neurons releasing the neurotransmitter dopamine in the striatum perturbs the initiation of movements and provokes debilitating motor symptoms. Treatments strategies for PD still mostly rely on the repetitive administration of levodopa to compensate for the lack of dopamine release. In the past decade, electrical stimulation of deep brain structures involved in compensatory elements of the implicated circuitry has proved efficient to relieve motor impairments. However, this technology requires invasive and complicated surgical procedures, fostering the development of alternative strategies.

Preclinical validation of effective treatments is mainly hampered by the lack of animal models closely replicating PD pathogenesis. Such models are needed to determine whether the treatment at hand can halt the progression of the degenerative process, and/or restore conditions allowing for a normalized motor function. The present project will use adeno-associated viral vectors (AAV) to express genetic mutations linked with familial PD into the substantia nigra pars compacta (SNpc) of rats and primates as mammalian model systems to induce brain pathologies as close as possible to the human condition. Emphasis will be placed in generating and measuring the induction of motor symptoms reminiscent of PD pathology. Next, these model systems will be used for in-depth analysis of corresponding defects in brain electrical activity patterns using advanced electrophysiological recordings. Ultimately, interventions aiming at electrical stimulation of sensory afferents in the dorsal surface of the spinal cord will be tested for their ability to revert the observed motor impairments.
 

Prof. P. Aebischer

Prof. M. Nicolelis