PLCγ1 in dopamine neurons critically regulates striatal dopamine release via VMAT2

Abstract

Dopamine, one of the essential neuromodulators, plays important roles in voluntary movement, reward, and motivation. Dysfunction of dopaminergic neurons are related to various psychological and neurodegenerative diseases. Therefore, understanding the detailed signaling mechanisms functionally affecting dopaminergic neurons is crucial for the development of better therapeutic strategies against dopamine-related disorders. Phospholipase Cγ1 (PLCγ1) is a key enzyme in the intracellular signaling that regulates diverse neuronal functions in the brain. However, physiological function of PLCγ1 in dopaminergic neurons is still unclear. In this study, we focused on the dopaminergic neuron-specific regulatory function of PLCγ1 in vivo. Interestingly, we found that the genetic deletion of PLCγ1 in dopaminergic neurons increased dopamine release from dopaminergic axon terminals. Expressions of tyrosine hydroxylase (TH) and dopamine transporter (DAT) were not changed but the expression and co-localization of vesicular monoamine transporter 2 (VMAT2) at dopaminergic axons were significantly increased in PLCγ1 conditional knockout mice. Moreover, expression of synapsin 3, which is one of synaptic vesicle trafficking regulators, was also increased in the striatum by loss of PLCγ1. Our findings suggest that PLCγ1 in dopamine neurons could modulate dopamine release at axon terminals by directly or indirectly interacting with synaptic machinery including VMAT2 and synapsin 3.