Stimulation of the cerebellum for the treatment of Parkinson’s disease and dyskinesia – CereDySTim

To answer our questions, we use a multidisciplinary approach based on optogenetic methods (mouse line that expresses the channel-rhodopsin in Purkinje cells), behavioral (motor tests) and in vivo electrophysiology in the motor circuit in animal models of the disease.

Dyskinesias induced by levodopa have already been studied in rodents. These dyskinesias were characterized in mice which show orolingual hyperkinetic movements, and axial rotation of the side contralateral to the dopamine lesion in the first administration of Levodopa and remain at the same intensity throughout the treatment period. Until now, the role of the cerebellum in these dyskinesias was not examined.
We have very encouraging preliminary results obtained with my Master 2 student Adele Bousquet, who showed a suppresion of dyskinetic movements after orolingual specific optogenetic stimulation of the Crus II oro-lingual area of the cerebellum (Figure 1). We need to confirm these data, but they suggest a strong beneficial effect of cerebellar stimulation. In addition, similar to findings in humans, this effect extends over the week following the cessation of stimulation.

The final perspective of this project is to evaluate the potential of the cerebellum as a therapeutic target in Parkinson's disease.

Research Master 2 Adèle Bousquet and Anaëlle Romagny
one paper in revision

Parkinson’s disease is one of the main neurodegenerative disorders with prevalence higher than 2% over 65 years. This disease is caused by the degeneration of a small set of neurons and the consecutive brain depletion in a neurotransmitter, the dopamine. The treatment of patients with a dopamine precursor drastically improves some, but not all, of the symptoms of the disease, and as the neuro-degeneration progresses, side effects develop and reduce the benefit of the treatment. Substantial functional reorganization takes place in the motor system in the course of the disease, in the cortical motor areas and within the two main subcortical afferents to these areas: the basal ganglia –where the degeneration takes place- and the cerebellum. By using pharmacological manipulations, optogenetics and in vivo electrophysiology techniques in behaving animals, we wish to assess the contribution of the cerebellum to the motor impairments in the disease and in the side effects of the treatment in the late phase of the disease. My goal is to analyze the pathophysiology of Parkinson’s disease and to propose novel, cost-effective, adjunctive therapies to improve the patient’s condition. Cerebellar stimulations may induce long-lasting plastic changes in the brain motor circuit. Thus, I will explore their therapeutic potential in animal models. Cerebellar-specific stimulation will be obtained with light illumination (that mimic the transcranial magnetic stimulation technique in patients) of the cerebellum in transgenic mice expressing light-gated ion channels. The impact of such stimulations on the functional connectivity of the brain motor circuits will be characterized. My project will examine the impact of cerebellar stimulations on a number of candidate symptoms of the disease (deficits in postural adjustments, gate initiation and the temporal coordination of muscle activity) and side effects of the pharmacological treatment (genesis of disabling involuntary movements). Finally, I will examine how the cerebellar control of sensory-motor cortical integration is recruited and potentially altered in Parkinson’s disease. The combination of optogenetics and in vivo electrophysiology in the motor circuit in behaving animals will thus allow us to understand the functional impact of cerebellar stimulations in Parkinson’s disease and to propose potential protocols for therapeutic approaches.