Parkinson’s disease (PD) is a global health challenge predominantly affecting the elderly, characterized mainly by motor deficits and a substantial decrease in quality of life. The motor symptoms of PD result from the loss of central dopaminergic innervation. Currently, the most widely used treatment is oral administration of L-DOPA, which – in the absence of dopamine fibers – is taken up by serotonergic fibers and released as dopamine in a process known as “false” release. Over time, this treatment leads to the development of levodopa-induced dyskinesia, a debilitating motor complication in patients. This phenomenon has been extensively documented in the striatum, a brain region significantly impacted by the dopaminergic depletion characteristic of PD, where serotonergic fibers proliferate after dopamine depletion. Our recent findings have demonstrated that serotonergic fibers in the substantia nigra pars reticulata (SNr), a key output nucleus of the basal ganglia, also exhibit significant proliferation following dopamine depletion. Building on this discovery, our research aims to systematically investigate both the time course of this serotonergic hyper-innervation and how this adaptive proliferation affects the intrinsic properties of SNr neurons and modulates their synaptic inputs. Furthermore, using acute brain slices, we will explore how these changes directly influence dopamine and serotonin secretion after L-DOPA administration, utilizing multiphoton imaging to monitor fluorescent monoamine indicators in vitro. This study will provide new insights into the critical role of neurotransmitter dynamics in PD and their interaction, as well as offer a fresh perspective on the neurophysiological consequences induced by the current gold-standard treatment for PD.

supervisor: Joshua Goldberg