Parkinson´s disease: interplay of cells and circuits in the genesis of movement disorders

In Parkinson’s disease (PD), loss of dopamine (DA) in the striatum causes poverty of movement (hypokinesia) while DA replacement therapy with L-DOPA can cause excessive abnormal movement (dyskinesia).

SPECIFIC AIMS: (1) To define alterations in striatal activation dynamics underlying specific motor abnormalities. (2) To develop new rodent models of PD having an improved construct validity and utilise these models in order to verify interesting mechanisms and test potential treatments. (3) To dissect the involvement of glial cells in the altered striatal dynamics.

METHODS: (1) Kinematic analyses and machine-learning are used to parse hypokinesia, hyperkinesia, and dystonia in rodent models of PD and L-DOPA-induced dyskinesia (LID); fiber photometry with fluorescent calcium indicators plus other methods are used to study the activity of specific neurons while animals exhibit movement abnormalities; optogenetic or chemogenetic approaches are used to alter the activity of specific cells. (2) Brain inoculation of pathogenic proteins is combined with neurotoxins to create PD-relevant pathology; animals receive clinically relevant regimens of pharmacological treatments followed by behavioural-physiological analyses. (3) Glial molecular profiling and calcium imaging are applied to various models.

SIGNIFICANCE: The results will catalyse a new comprehension of movement disorders associated with basal ganglia disease and pave the way for the development of personalized treatments.