Reversal of pathological motor behavior in a model of Parkinson’s disease by striatal dopamine uncaging

Abstract

Motor deficits observed in Parkinson’s disease (PD) are caused by the loss of dopaminergic neurons and the subsequent dopamine depletion in different brain areas. The most common therapy to treat motor symptoms for patients with this disorder is the systemic intake of L-DOPA that increases dopamine levels in all the brain, making it difficult to discern the main locus of dopaminergic action in the alleviation of motor control. Caged compounds are molecules with the ability to release neuromodulators locally in temporary controlled conditions using light. In the present study, we measured the turning behavior of unilateral dopamine-depleted mice before and after dopamine uncaging. The optical delivery of dopamine in the striatum of lesioned mice produced contralateral turning behavior that resembled, to a lesser extent, the contralateral turning behavior evoked by a systemic injection of apomorphine. Contralateral turning behavior induced by dopamine uncaging was temporarily tied to the transient elevation of dopamine concentration and was reversed when dopamine decreased to pathological levels. Remarkably, contralateral turning behavior was tuned by changing the power and frequency of light stimulation, opening the possibility to modulate dopamine fluctuations using different light stimulation protocols. Moreover, striatal dopamine uncaging recapitulated the motor effects of a low concentration of systemic L-DOPA, but with better temporal control of dopamine levels. Finally, dopamine uncaging reduced the pathological synchronization of striatal neuronal ensembles that characterize unilateral dopamine-depleted mice. We conclude that optical delivery of dopamine in the striatum resembles the motor effects induced by systemic injection of dopaminergic agonists in unilateral dopamine-depleted mice. Future experiments using this approach could help to elucidate the role of dopamine in different brain nuclei in normal and pathological conditions.