Thesis – Gawain GRELLIER

Genetically controlled apoptosis of dopaminergic neurons: correction of sensorimotor deficits using a T-type calcium channel inhibitor

Jury

• Pascal FOSSAT, Professor, Institute for Neurodegenerative Diseases, Bordeaux – Reviewer
• Michel BARROT, Research Director, Institute of Cellular and Integrative Neuroscience, Strasbourg – Reviewer
• Gaëtan POULEN, Professor-Hospital Physician, University of Montpellier – Examiner
• Véronique COIZET, Research Scientist, Grenoble Institut des Neurosciences – Examiner
• Amaury FRANÇOIS, Research Scientist, IGF, University of Montpellier – Co-supervisor
• Emmanuel BOURINET, Research Director, IGF, University of Montpellier – Thesis supervisor

Summary

Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Beyond motor symptoms, it involves sensory abnormalities and chronic pain, which often appear early and resist dopaminergic treatments. However, current preclinical models mostly mimic advanced stages induced instantaneously, which limits the study of early disease phases. We exploited the caspase-3 pathway, the main mediator of apoptosis in these neurons, by expressing an inducible caspase-3 (taCasp3) specifically in SNc dopaminergic neurons using the CreERT2 system (TH-CreERT2 mice). Increasing tamoxifen doses allow progressive, specific ablation, in order to establish a causal link with the sequence of sensory and then motor deficits. Strong induction caused marked SNc degeneration in both male and female mice, with motor deficits and mechanical hypersensitivity. Progressive ablation showed that tactile allodynia appears well before motor symptoms. Finally, a blood-brain barrier-penetrant T-type calcium channel inhibitor acutely reversed this tactile hypersensitivity. This model faithfully reproduces the clinical timeline of sensory and motor signs in PD and is a promising tool to investigate the mechanisms of parkinsonian pain and to evaluate therapies targeting non-motor symptoms.