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Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by the loss of dopamine (DA) producing neurons in the substantia nigra pars compacta (SNc), resulting in typical motor symptoms. DA replacement with L-DOPA is the standard therapy for PD. However, with treatment duration many patients face the severe treatment complication of L-DOPA-induced dyskinesia (LID), constituting in abnormal involuntary movements (AIMs). The etiology of PD and LID is largely unknown, but both pathophysiological states are linked to DA. How neurons in a DA-receptive brain region adapt to the pathophysiological states of PD and LID is the topic of this thesis’ work.

The striatum is the “hub” into the basal ganglia network and implicated in movement control. Striatal spiny projection neurons (SPNs) divide into two subpopulations, forming the so-called direct and indirect pathway of the basal ganglia. Due to the expression of different DA receptors, direct and indirect pathway SPNs (dSPNs and iSPNs, respectively) are oppositely modulated by DA.

D1 receptor (D1R) stimulation in the DA-denervated, parkinsonian striatum leads to a supersensitive activation of ERK1/2 in dSPNs. This aberrant signaling activation is widely believed to be a core mechanism leading to the development of LID. In the first study we investigated which signaling pathways participate in this D1R-induced ERK1/2 activation. We found a distinct and complex interaction between PKA- and Ca2+-dependent pathways, which is critically modulated by mGluR5. In the second study we further investigated the antidsykinetic profile of mGluR5 antagonist treatment, finding that the …