Dr. James Maas, MD

2018 Hellman Fellow

James.Maas@ucsf.edu

Assistant Clinical Professor, Department of Neurology
UCSF

Project Title: The Regulation of Dopamine Release

Project Summary:

The neurotransmitter dopamine (DA) plays a crucial role in normal physiology, motor control, and behavior. Dysfunctional DA signaling contributes to human neuropsychiatric disease, from Parkinson’s disease to drug addiction. DA signaling differs in important ways from other neurotransmitters, and the mechanisms responsible remain poorly understood. DA has been thought to act by volume transmission, as opposed to synaptic transmission. Furthermore, DA neurons exhibit two distinct modes of firing and DA release in vivo is strongly frequency-dependent. The long-term objective of this proposal is to elucidate the mechanisms that account for the unusual properties of DA release and manipulate these mechanisms to understand how DA signals to regulate behavior. The strategy of this proposal is to manipulate the sites of DA storage through mutations that affect the sorting of the vesicular monoamine transporter 2 (VMAT2) to synaptic vesicles. Since the adaptor protein AP-3 is specifically required for the assembly of dopaminergic vesicles, I hypothesize that the AP-3-dependent trafficking of VMAT2 to a specific population of synaptic vesicles confers the frequency dependence of DA release. In this proposal, I will use live imaging in cultured DA neurons to determine how AP-3 influences the exocytosis of VMAT2+ vesicles.  I have made a novel knock-in mouse model containing mutations in VMAT2 that specifically alter its AP-3-dependent trafficking. Using this mouse model, I will utilize fast scan cyclic voltammetry and whole cell recording to determine how AP-3 dependent sorting of VMAT2 regulates the frequency dependence of DA release in the striatum.