Synaptotagmin-1 is the Ca2+ sensor for fast striatal dopamine release.

Aditi Banerjee,Paulina Nemcova,Pascal S Kaeser,Changliang Liu,Jinoh Lee

doi:10.7554/elife.58359

Abstract

Dopamine powerfully controls neural circuits through neuromodulation. In the vertebrate striatum, dopamine adjusts cellular functions to regulate behaviors across broad time scales, but how the dopamine secretory system is built to support fast and slow neuromodulation is not known. Here, we set out to identify Ca2+-triggering mechanisms for dopamine release. We find that synchronous dopamine secretion is abolished in acute brain slices of conditional knockout mice in which Synaptotagmin-1 is removed from dopamine neurons. This indicates that Synaptotagmin-1 is the Ca2+ sensor for fast dopamine release. Remarkably, dopamine release induced by strong depolarization and asynchronous release during stimulus trains are unaffected by Synaptotagmin-1 knockout. Microdialysis further reveals that these modes and action potential-independent release provide significant amounts of extracellular dopamine in vivo. We propose that the molecular machinery for dopamine secretion has evolved to support fast and slow signaling modes, with fast release requiring the Ca2+ sensor Synaptotagmin-1.

Highlights

Dopamine is an important neuromodulator in the vertebrate brain, but the secretory biology of dopamine is not well understood
Knockdown of Synaptotagmin-1, –4 or –7 resulted in partial impairments of [3H]-dopamine released into the supernatant in response to KCl depolarization of cultured midbrain neurons, and BDNF release is modulated by Synaptotagmin-4, but at least Synaptotagmin-4 is unlikely to operate as Banerjee et al eLife 2020;9:e58359
We find that fast dopamine secretion is abolished in the striatum of mouse mutants that lack Synaptotagmin-1 in dopamine neurons, and conclude that Synaptotagmin-1 is the Ca2+ sensor for fast dopamine release

Summary

Introduction

Dopamine is an important neuromodulator in the vertebrate brain, but the secretory biology of dopamine is not well understood. A key dopamine pathway arises from midbrain dopamine neurons located in the substantia nigra pars compacta. Their axons send projections to the dorsal striatum, where dopamine neuromodulation controls initiation and execution of movement. Fast synaptic transmission relies on Synaptotagmin-1, –2 or –9 (Fernandez-Chacon et al, 2001; Sun et al, 2007; Xu et al, 2007) Synapses without these fast Synaptotagmins have prominent asynchronous release (Turecek and Regehr, 2019). We find that fast dopamine secretion is abolished in the striatum of mouse mutants that lack Synaptotagmin-1 in dopamine neurons, and conclude that Synaptotagmin-1 is the Ca2+ sensor for fast dopamine release

Results and discussion

A Syt-1 control zy x Syt-1 control

Materials and methods

Funding Funder