Alexandra Nelson

Parkinson's disease (PD) is characterized by progressive neurodegeneration, which is associated with motor and non-motor symptoms. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), characterized by pathological gambling, hypersexuality, and/or compulsive shopping. Approximately 14-40% of all medicated PD patients suffer from ICD. Despite the high prevalence of ICD in medicated PD patients, we know little of its mechanisms, and the main therapeutic strategy is reducing or eliminating dopamine agonist medication. Human imaging studies suggest that the input nucleus of the basal ganglia, the striatum, may be a critical site of circuit dysfunction in ICD. To explore the cellular and circuit mechanisms of ICD, we developed a mouse model in which we administered the dopamine D2/3 agonist pramipexole to parkinsonian and healthy control mice. ICD-like behavior was assessed using a delay discounting task. Delay discounting is a normal cognitive phenomenon, in which the value of a reward decreases according to the time needed to wait for it. Impulsivity is measured as the preference for immediate (small) over delayed (large) rewards. We combined this mouse model with chemogenetics and *in vivo* optically-identified single-unit recordings to examine how dopamine agonists act on vulnerable striatal circuitry to mediate impulsive decision-making. We found that in parkinsonian mice, therapeutic doses of dopamine D2/3R or D1R agonists drove more pronounced delay discounting, reminiscent of what has been reported in PD/ICD patients on medication. In contrast, healthy mice did not become more impulsive when given the same dose of dopamine agonist. The clinically relevant dopamine D2/3R agonist pramipexole induced marked bidirectional changes in the firing of striatal direct and indirect pathway neurons in parkinsonian mice. Chronic pramipexole treatment potentiated these changes in striatal physiology and decision-making behavior. Furthermore, chemogenetic excitation of direct pathway striatal neurons or inhibition of indirect pathway neurons induced impulsive decision making in the absence of dopamine agonists. These findings indicate that abnormal striatal activity plays a causal role in mediating ICD-like behaviors. Together, they provide a robust mouse model and insights into ICD pathophysiology.

The burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. At many synapses, however, high firing rates deplete synaptic vesicles (SVs), resulting in synaptic depression that limits release. What accounts for the increased release of dopamine by stimulation at high frequency? We find that adaptor protein-3 (AP-3) and its coat protein VPS41 promote axonal dopamine release by targeting vesicular monoamine transporter VMAT2 to the axon rather than dendrites. AP-3 and VPS41 also produce SVs that respond preferentially to high-frequency stimulation, independent of their role in axonal polarity. In addition, conditional inactivation of VPS41 in dopamine neurons impairs reinforcement learning, and this involves a defect in the frequency dependence of release rather than the amount of dopamine released. Thus, AP-3 and VPS41 promote the axonal polarity of dopamine release but enable learning by producing a distinct population of SVs tuned specifically to high firing frequency that confers the phasic release of dopamine.