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, and their dysfunction is closely linked to various psychological and neurodegenerative diseases. Hence, understanding the detailed signaling mechanisms that functionally modulate dopamine neurons is crucial for the development of better therapeutic strategies against dopamine-related disorders. Phospholipase C gamma 1 (PLC gamma 1) is a key enzyme in intracellular signaling that regulates diverse neuronal functions in the brain. It was proposed that PLC gamma 1 is implicated in the development of dopaminergic neurons, while the physiological function of PLC gamma 1 remains to be determined. In this study, we investigated the physiological role of PLC gamma 1, one of the key effector enzymes in intracellular signaling, in regulating dopaminergic function in vivo. We found that cell type-specific deletion of PLC gamma 1 does not adversely affect the development and cellular morphology of midbrain dopamine neurons but does facilitate dopamine release from dopaminergic axon terminals in the striatum. The enhancement of dopamine release was accompanied by increased colocalization of vesicular monoamine transporter 2 (VMAT2) at dopaminergic axon terminals. Notably, dopamine neuron-specific knockout of PLC gamma 1 also led to heightened expression and colocalization of synapsin III, which controls the trafficking of synaptic vesicles. Furthermore, the knockdown of VMAT2 and synapsin III in dopamine neurons resulted in a significant attenuation of dopamine release, while this attenuation was less severe in PLC gamma 1 cKO mice. Our findings suggest that PLC gamma 1 in dopamine neurons could critically modulate dopamine release at axon terminals by directly or indirectly interacting with synaptic machinery, including VMAT2 and synapsin III. Dopamine release is significantly increased in mice lacking the phospholipase C gamma 1 (PLC gamma 1) enzyme in their dopamine neurons, according to a study by researchers at the Ulsan National Institute of Science and Technology. The team found that PLC gamma 1 conditional knockout mice exhibited normal dopamine neuron development and cellular structures, but showed enhanced dopamine release. This was potentially due to increased localization of vesicular monoamine transporter 2 (VMAT2) and synapsin III in dopaminergic axons. The findings suggest that PLC gamma 1 plays a critical role in regulating dopamine release by potentially modulating synaptic vesicle trafficking in dopamine neurons.