Resilience, Dysregulation, and Rescue of Basal Ganglia Indirect Pathway Function in Progressive Parkinsonism

While the bradykinetic and akinetic symptoms of Parkinson’s disease (PD) are clearly linked to the degeneration of substantia nigra dopaminergic (SN DAergic) neurons1-3, the mechanisms that underlie the emergence and escalation of basal ganglia circuit and motor dysfunction remain poorly defined. Degeneration of SN DAergic neurons long precedes the expression of symptoms in PD4-6. At the point of diagnosis ~50-75% of nigrostriatal DAergic axons and ~30% of SN DAergic neurons no longer express DA cell markers or have been lost7,8, arguing for an extensive prodromal period, masked by compensatory mechanisms9-25. As degeneration proceeds, increasingly dysregulated activity24,26-41 and maladaptive plasticity13-24 within the indirect pathway may progressively degrade basal ganglia computation, leading to motor deficits17,18,26-28,36-40. This circuit pathophysiology has also been suggested as an additional source of bioenergetic stress in SN DAergic neurons that could accelerate their degeneration42-47. Although plausible, these concepts cannot be rigorously studied in acute toxin models that mimic the absence of DA in advanced PD but not the spatiotemporal pattern of DAergic neuron degeneration in patients48,49. To fill this gap, we propose to examine the emergence of parkinsonism and its impact of indirect pathway function in the MitoPark model of PD50. MitoPark mice are generated through genetic deletion of the nuclear encoded mitochondrial transcription factor TFAM in DAergic neurons, which causes mitochondrial dysfunction50-52, a consistent vulnerability of these cells in familial and sporadic forms of PD53-58. These mice recapitulate key aspects of PD, including: 1) progressive SN DAergic neuron degeneration and levodopa-sensitive motor deficits, but within a compressed, experimentally tractable time frame spanning 6- 7 months50,51,59; 2) relative susceptibility of SN DAergic neuron axon terminals in the dorsal striatum in the initial stages of parkinsonism50,52,59-61; 3) relative susceptibility of SN versus ventral tegmental area DAergic neurons50,51,59; 4) circuit plasticity and pathophysiology analogous to that in advanced PD and its models (pilot data). Using in vivo and ex vivo electrophysiological, optogenetic, chemogenetic, 2-photon imaging, electrochemical, immunohistochemical, and behavioral approaches, we propose 3 specific aims: 1) determine the mechanisms responsible for the retention of indirect pathway and motor function in prodromal MitoPark mice; 2) determine the mechanisms underlying progressive indirect pathway and motor dysfunction in symptomatic MitoPark mice; 3) determine whether motor dysfunction and degeneration of SN DAergic neurons can be rescued in symptomatic MitoPark mice by chemogenetically manipulating indirect pathway activity. Through the execution of this research, we will learn why aspects of basal ganglia indirect pathway function are initially resilient to but ultimately dysregulated by degeneration of SN DAergic neurons, and whether chemogenetic indirect pathway manipulation is an effective symptomatic and/or disease-modifying therapy for parkinsonism.