PLCγ1 in dopamine neurons critically regulates striatal dopamine release via VMAT2 and synapsin III

Abstract

Dopamine neurons are essential for voluntary movement, reward learning, and motivation, whose dysfunction isclosely linked to various psychological and neurodegenerative diseases such as Parkinson's disease. Henceunderstanding the detailed signaling mechanisms functionally modulating dopamine neurons is crucial for thedevelopment of better therapeutic strategies against dopamine-related disorders. Phospholipase Cγ1 (PLCγ1) is akey enzyme in intracellular signaling that regulates diverse neuronal functions in the brain. It was proposed thatPLCγ1 would be implicated in the development of dopaminergic neurons, while the physiological function ofPLCγ1 remains to be determined. In this study, we found that cell type-specific deletion of PLCγ1 does notadversely affect the development and cellular morphology of midbrain dopamine neurons but does facilitatedopamine release from dopaminergic axon terminals in the striatum. This enhancement of dopamine release wasaccompanied by increased co-localization of vesicular monoamine transporter 2 (VMAT2) at dopaminergic axons.Notably, dopamine neuron-specific knockout of PLCγ1 also led to the heightened expression and co-localization ofsynapsin III which controls the trafficking of synaptic vesicles. Our findings suggest that PLCγ1 in dopamineneurons could critically modulate dopamine release at axon terminals by directly or indirectly interacting withsynaptic machinery including VMAT2 and synapsin III.