Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder whose cardinal motor symptoms are attributed to dysfunction of basal ganglia circuits under conditions of low dopamine. Despite well-established physiological criteria to define basal ganglia dysfunction, correlations between individual parameters and motor symptoms are often weak, challenging their predictive validity and causal contributions to behavior. One limitation is that basal ganglia pathophysiology is studied only at end-stages of depletion, leaving an impoverished understanding of when deficits emerge and how they evolve over the course of depletion. In this study, we use toxin- and neurodegeneration-induced mouse models of dopamine depletion to establish the physiological trajectory by which the substantia nigra reticulata (SNr) transitions from the healthy to the diseased state. We find that physiological progression in the SNr proceeds in discrete state transitions that are highly stereotyped across models and correlate well with the prodromal and symptomatic stages of behavior.
Highlights
Parkinson’s disease (PD) is a movement disorder caused by the progressive degeneration of dopamine neurons in the substantia nigra pars compacta (SNc)
Recordings targeted to the substantia nigra reticulata (SNr) were confirmed by the presence of fast, tonically active units (~30–40% were modulated by movement), and by visualizing the recording track postmortem with immunostaining against the microglial marker, Iba-1 (Figure 1B)
Our study reveals that over the course of progressive dopamine loss, SNr dysfunction progresses through a series of discrete state transitions
Summary
Parkinson’s disease (PD) is a movement disorder caused by the progressive degeneration of dopamine neurons in the substantia nigra pars compacta (SNc). The ‘rate model’ posits that motor symptoms are the result of elevated firing rates of basal ganglia output neurons under dopamine depleted conditions (Albin et al, 1989; DeLong, 1990). PD is a gradual, neurodegenerative disorder and motor symptoms rarely present until late stages of dopamine loss (~20–30% striatal dopamine remaining) (Bernheimer et al, 1973; Fahn, 2003; Riederer and Wuketich, 1976). In the moderate pathophysiological state, the SNr is robust to continued decreases in dopamine levels, possibly reflecting compensatory plasticity, until undergoing a final state transition into the ‘severe’ pathophysiological state when dopamine levels drop below 25–35% remaining These results reveal key inflection points in the progression of basal ganglia pathophysiology that correlate with symptomatic manifestation over the course of progressive dopamine loss
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