In vivo study of the functional role of brain adenosine 2A and glutamate mGLuR5 receptors in movement disorders

Parkinson’s disease (PD) and Huntington’s disease (HD) are movement disorders, without effective therapy. Dopamine deficiencies play a major role in these disorders, but also the brain adenosine and glutamate systems are dysregulated. Ex vivo studies point towards a role of the adenosine 2A receptor (A2A-R) in the pathogenesis of PD and HD, especially on the motor and cognitive domains. The metabotropic glutamate receptor type 5 (mGLuR5) contribute to excitotoxicity, and interact with A2A-R to counter effects of dopamine in basal ganglia signaling. I wish to study the relative contribution of A2A-R and mGluR5 as key effectors of the adenosine and glutamate systems in the pathophysiology of PD and HD in vivo. Their relative importance is currently unknown but need to be identified to provide proof-of-mechanism for neuroprotective, cognitive or motor-related treatment. I will address this by means of very novel imaging substances (‘tracers’) that allow measurements and imaging of the involved proteins in the brain using Positron Emission Tomography (PET). Combined with behavioral correlates, genetics and microdialysis, my research aims for in vivo (pre)clinical biomarkers and methods for the evaluation of neuroprotective strategies. I will learn how these systems work and interact, and how realistic it is to develop medication, or to predict and even prevent disease development.