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Neuron. 2017 Aug 30;95(5):1074-1088.e7. doi: 10.1016/j.neuron.2017.07.038. Epub 2017 Aug 17.

Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT.

Author information

1
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
2
Department of Chemistry, Columbia University, New York, NY 10027, USA.
3
Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA.
4
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
5
Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA; Department of Neurology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
6
Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine University of California, Los Angeles, CA 90095, USA.
7
Brain Mind Institute, EPFL, 1015 Lausanne, Switzerland.
8
Center for Motor Neuron Biology and Disease, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
9
Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
10
Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA; Department of Pharmacology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
11
Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA; Department of Neurology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Department of Pharmacology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
12
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: freyberg@pitt.edu.

Abstract

The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content.

KEYWORDS:

VGLUT2; depolarization; dopamine; glutamate; neurotransmission; pH; presynaptic; synaptic vesicle; vesicle content

PMID:
28823729
PMCID:
PMC5760215
DOI:
10.1016/j.neuron.2017.07.038
[Indexed for MEDLINE]
Free PMC Article

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