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 is closely related to various psychological and neurodegenerative diseases. Therefore, understanding the detailed signaling mechanisms functionally modulating dopamine neurons is crucial for the development of better therapeutic strategies against dopamine- related disorders. In this study, we investigate the physiological role of phospholipase Cγ1 (PLCγ1), one of the key effector enzymes in intracellular signaling, on regulating dopaminergic function in vivo. We found that cell type-specific deletion of PLCγ1 did not adversely affect morphology and structure of midbrain dopamine neurons but did facilitate dopamine release from dopaminergic axon terminals in the striatum. Elevated dopamine release was accompanied 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 of synapsin III that controls the trafficking of synaptic vesicles. Our findings suggest that PLCγ1 in dopamine neurons could critically modulate dopamine release at axon terminals by directly or indirectly interacting with synaptic machinery including VMAT2 and synapsin III.