# Mechanisms of Vesicle Docking and Priming for Striatal Dopamine Release

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2020 · $33,283

## Abstract

Signaling in the nervous system relies on the transfer of chemical signals from one neuron to the next. There
are two main classes of these signals: fast neurotransmitters and neuromodulators. Fast neurotransmitters are
released from specialized release sites and bind directly to receptors on the opposing post-synaptic membrane
to exert an instant change in the membrane potential of the post-synaptic cell. In contrast, neuromodulators are
released slowly and diffuse through the extracellular space. They bind to receptors on several cells at once to
exert long-lasting changes in a population of neurons. The mechanisms in the secretory pathway for
neuromodulators are not well understood. Extensive research from many laboratories on the release of fast
neurotransmitters has found that a complex of proteins at the presynaptic membrane, known as the active zone,
morphologically docks and functionally primes synaptic vesicles for rapid and precise release. Here I focus on
release mechanisms of dopamine, a neuromodulator critical for movement, reward, and emotion. We have
recently found that an active zone-like complex of proteins is required for unexpectedly rapid dopamine release.
The requirement of a release site strongly suggests that dopamine vesicles are positioned close to their future
sites of release and are rendered release ready, reminiscent of the docking and priming of synaptic vesicles. I
hypothesize that the specialized, active zone-like release site in dopamine neurons both docks and
primes dopamine vesicles to allow for fast exocytosis upon action potential triggering. I will dissect these
two processes on a functional and structural level. In aim 1, I will characterize the role of the priming protein,
Munc13 in dopamine release. My preliminary data suggests that Munc13 is essential for dopamine release. I will
use carbon fiber amperometry, super resolution and confocal microscopy, and mouse genetics to systematically
characterize the localization and function of Munc13 in dopamine neurons. In aim 2, I will characterize vesicle
docking in dopamine axons and in mutant mice that lack potential docking proteins. To unambiguously identify
dopamine terminals, I will employ conditional tagging of vesicles with horseradish peroxidase (HRP) for cell-type
identification in electron microscopic images. I will then use serial EM to 3D-reconstruct striatal dopamine axons.
In summary, the experiments proposed here will contribute to a novel mechanistic understanding of the
dopamine secretory pathway. Our finding that dopamine release occurs rapidly and precisely signals the
beginning of a paradigm shift for dopamine transmission. The proposed work expands on dissecting the make-
up and function of the rapid exocytotic machinery for dopamine. Precise understanding of dopamine secretion
will also provide new insights into how dopamine signaling may break down in neurological disease.

## Key facts

- **NIH application ID:** 9849130
- **Project number:** 5F31NS105159-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Lauren Hayley Kershberg
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,283
- **Award type:** 5
- **Project period:** 2018-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849130

## Citation

> US National Institutes of Health, RePORTER application 9849130, Mechanisms of Vesicle Docking and Priming for Striatal Dopamine Release (5F31NS105159-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9849130. Licensed CC0.

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