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

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Aditi Banerjee ◽  
Jinoh Lee ◽  
Paulina Nemcova ◽  
Changliang Liu ◽  
Pascal S Kaeser
Keyword(s):  
Dopamine Release ◽  
Brain Slices ◽  
Conditional Knockout ◽  
Dopamine Neurons ◽  
Cellular Functions ◽  
Synaptotagmin 1 ◽  
Molecular Machinery ◽  
Asynchronous Release ◽  
Secretory System

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.

scholarly journals Dopamine in the basal amygdala signals salient somatosensory events during fear learning

2019 ◽  
Author(s):  
Wei Tang ◽  
Olexiy Kochubey ◽  
Michael Kintscher ◽  
Ralf Schneggenburger
Keyword(s):  
Memory Retrieval ◽  
Dopamine Release ◽  
Brain Area ◽  
Dopamine Neurons ◽  
Fear Learning ◽  
Dopamine Concentration ◽  
Axon Terminals ◽  
Basal Amygdala ◽  
Teaching Signal

SummaryThe amygdala is a brain area critical for the formation of threat memories. However, the nature of the teaching signal(s) that drive plasticity in the amygdala are still under debate. Here, we use optogenetic methods to investigate whether dopamine release in the amygdala contributes to fear learning. Antero- and retrograde labeling showed that a sparse, and relatively evenly distributed population of ventral tegmental area (VTA) neurons projects to the basal amygdala (BA). In-vivo optrode recordings in behaving mice showed that many VTA neurons, amongst them putative dopamine neurons, are excited by footshocks. Correspondingly, in-vivo fiber photometry of dopamine in the BA revealed robust dopamine concentration transients upon footshock presentation. Finally, silencing VTA dopamine neurons, or their axon terminals in the BA during the footshock, reduced the extent of threat memory retrieval one day later. Thus, VTA dopamine neurons projecting to the BA code for the saliency of the footshock event, and the resulting dopamine release in the BA facilitates threat memory formation.

scholarly journals Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of DYT1-TOR1A dystonia

2020 ◽  
Author(s):  
Anthony M. Downs ◽  
Xueliang Fan ◽  
Radhika Kadakia ◽  
Yuping Donsante ◽  
H.A. Jinnah ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Ex Vivo ◽  
Dopamine Neurons ◽  
Striatal Dopamine ◽  
Cholinergic Interneurons ◽  
Base Pair Deletion ◽  
Presynaptic Mechanisms ◽  
Conditional Expression ◽  
Striatal Dopamine Release

ABSTRACTDYT1-TOR1A dystonia is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a(ΔE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(ΔE) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a(ΔE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(ΔE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a+/ΔE knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(ΔE) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca2+ signaling, D2 dopamine autoreceptor function and GABAB receptor function, are intact. Although the mechanistic link between Tor1a(ΔE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(ΔE) mutation within dopamine neurons.

scholarly journals Inferring spikes from calcium imaging in dopamine neurons

2020 ◽  
Author(s):  
Weston Fleming ◽  
Sean Jewell ◽  
Ben Engelhard ◽  
Daniela M. Witten ◽  
Ilana B. Witten
Keyword(s):  
Virtual Reality ◽  
Pavlovian Conditioning ◽  
Calcium Imaging ◽  
Brain Slices ◽  
Neural Correlates ◽  
Dopamine Neurons ◽  
Inference Algorithm ◽  
Inference Methods ◽  
Spike Patterns

AbstractCalcium imaging has led to discoveries about neural correlates of behavior in subcortical neurons, including dopamine (DA) neurons. However, spike inference methods have not been tested in most populations of subcortical neurons. To address this gap, we simultaneously performed calcium imaging and electrophysiology in DA neurons in brain slices, and applied a recently developed spike inference algorithm to the GCaMP fluorescence. This revealed that individual spikes can be inferred accurately in this population. Next, we inferred spikes in vivo from calcium imaging from these neurons during Pavlovian conditioning, as well as during navigation in virtual reality. In both cases, we quantitatively recapitulated previous in vivo electrophysiological observations. Our work provides a validated approach to infer spikes from calcium imaging in DA neurons, and implies that aspects of both tonic and phasic spike patterns can be recovered.

scholarly journals Glial Cell Line–Derived Neurotrophic Factor Receptor Rearranged During Transfection Agonist Supports Dopamine Neurons In Vitro and Enhances Dopamine Release In Vivo

2019 ◽  
Vol 35 (2) ◽  
pp. 245-255 ◽  
Author(s):  
Arun Kumar Mahato ◽  
Jaakko Kopra ◽  
Juho‐Matti Renko ◽  
Tanel Visnapuu ◽  
Ilari Korhonen ◽  
...  
Keyword(s):  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Dopamine Release ◽  
Dopamine Neurons

scholarly journals Hyperexcitable Substantia Nigra Dopamine Neurons in PINK1- and HtrA2/Omi-Deficient Mice

2010 ◽  
Vol 104 (6) ◽  
pp. 3009-3020 ◽  
Author(s):  
Matthew W. Bishop ◽  
Subhojit Chakraborty ◽  
Gillian A. C. Matthews ◽  
Antonios Dougalis ◽  
Nicholas W. Wood ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Brain Slices ◽  
Selective Vulnerability ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Electrophysiological Properties ◽  
Irregular Pattern ◽  
Functional Reduction ◽  
Small Conductance

The electrophysiological properties of substantia nigra pars compacta (SNC) dopamine neurons can influence their susceptibility to degeneration in toxin-based models of Parkinson's disease (PD), suggesting that excitotoxic and/or hypoactive mechanisms may be engaged during the early stages of the disease. It is unclear, however, whether the electrophysiological properties of SNC dopamine neurons are affected by genetic susceptibility to PD. Here we show that deletion of PD-associated genes, PINK1 or HtrA2/Omi, leads to a functional reduction in the activity of small-conductance Ca2+-activated potassium channels. This reduction causes SNC dopamine neurons to fire action potentials in an irregular pattern and enhances burst firing in brain slices and in vivo. In contrast, PINK1 deletion does not affect firing regularity in ventral tegmental area dopamine neurons or substantia nigra pars reticulata GABAergic neurons. These findings suggest that changes in SNC dopamine neuron excitability may play a role in their selective vulnerability in PD.

scholarly journals Inferring spikes from calcium imaging in dopamine neurons

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252345
Author(s):  
Weston Fleming ◽  
Sean Jewell ◽  
Ben Engelhard ◽  
Daniela M. Witten ◽  
Ilana B. Witten
Keyword(s):  
Virtual Reality ◽  
Pavlovian Conditioning ◽  
Calcium Imaging ◽  
Brain Slices ◽  
Neural Correlates ◽  
Dopamine Neurons ◽  
Inference Algorithm ◽  
Inference Methods ◽  
Spike Patterns

Calcium imaging has led to discoveries about neural correlates of behavior in subcortical neurons, including dopamine (DA) neurons. However, spike inference methods have not been tested in most populations of subcortical neurons. To address this gap, we simultaneously performed calcium imaging and electrophysiology in DA neurons in brain slices and applied a recently developed spike inference algorithm to the GCaMP fluorescence. This revealed that individual spikes can be inferred accurately in this population. Next, we inferred spikes in vivo from calcium imaging from these neurons during Pavlovian conditioning, as well as during navigation in virtual reality. In both cases, we quantitatively recapitulated previous in vivo electrophysiological observations. Our work provides a validated approach to infer spikes from calcium imaging in DA neurons and implies that aspects of both tonic and phasic spike patterns can be recovered.

scholarly journals Synaptotagmin-7 enhances phasic dopamine release

2021 ◽  
Author(s):  
Skyler L Jackman ◽  
Sarah A Kissiwaa ◽  
Joseph J Lebowitz ◽  
Kim A Engeln ◽  
Anna M Bowman ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Dopamine Release ◽  
Low Frequency ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Short Term ◽  
Low Frequency Stimulation ◽  
Frequency Stimulation ◽  
Dopamine Signaling

Dopamine released from substantia nigra pars compacta (SNc) neurons modulates movement, motivation, and reward. In addition to their tonic firing pattern, dopamine neurons also fire high-frequency bursts that cause superlinear increases in dopamine release. To examine this poorly understood form of short-term plasticity, we used the fluorescent dopamine sensor dLight1.3b to examine the role of the calcium-binding protein synaptotagmin-7 (SYT7). We report that SYT7 mediates a hidden component of facilitation, which was unmasked by lowering initial release probability, or by low-frequency stimulation of nerve terminals. In Syt7 KO neurons, there was profound synaptic depression that significantly reduced release during stimulations that mimic in vivo firing patterns of SNc neurons. D2-mediated inhibitory postsynaptic currents in the SNc revealed a similar role for SYT7 in somatodendritic release. Our results indicate that SYT7 drives short-term facilitation of release from dopamine neurons, which likely underlies frequency-dependence of dopamine signaling in vivo.

scholarly journals The role of the C2A domain of synaptotagmin 1 in asynchronous neurotransmitter release

2020 ◽  
Author(s):  
Mallory C. Shields ◽  
Matthew R. Bowers ◽  
Hannah L. Kramer ◽  
McKenzie M. Fulcer ◽  
Lara C. Perinet ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Spatial Competition ◽  
Competition Hypothesis ◽  
Inhibition Hypothesis ◽  
Synaptotagmin 1 ◽  
Asynchronous Release ◽  
Opposing Effects ◽  
Insight Into

AbstractFollowing nerve stimulation, there are two distinct phases of Ca2+-dependent neurotransmitter release: a fast, synchronous release phase, and a prolonged, asynchronous release phase. Each of these phases is tightly regulated and mediated by distinct mechanisms. Synaptotagmin 1 is the major Ca2+ sensor that triggers fast, synchronous neurotransmitter release upon Ca2+ binding by its C2A and C2B domains. It has also been implicated in the inhibition of asynchronous neurotransmitter release, as blocking Ca2+ binding by the C2A domain of synaptotagmin 1 results in increased asynchronous release. However, the mutation used to block Ca2+ binding in the previous experiments (aspartate to asparagine mutations, sytD-N) had the unintended side effect of mimicking Ca2+ binding, raising the possibility that the increase in asynchronous release was an artifact of ostensibly constitutive Ca2+ binding. To directly test this C2A inhibition hypothesis, we utilized an alternate C2A mutation that we designed to block Ca2+ binding without mimicking it (an aspartate to glutamate mutation, sytD-E). Analysis of both the original sytD-N mutation and our alternate sytD-E mutation at the Drosophila neuromuscular junction showed differential effects on asynchronous release, as well as on synchronous release and the frequency of spontaneous release. Importantly, we found that asynchronous release is not increased in the sytD-E mutant. Thus, our work provides new mechanistic insight into synaptotagmin 1 function during Ca2+-evoked synaptic transmission and demonstrates that Ca2+ binding by the C2A domain of synaptotagmin 1 does not inhibit asynchronous neurotransmitter release in vivo.Significance statementThis study provides mechanistic insights into synaptotagmin function during asynchronous neurotransmitter release and supports a dramatically different hypothesis regarding the mechanisms triggering asynchronous vesicle fusion. Using two distinct C2A mutations that block Ca2+ binding, we report opposing effects on synchronous, spontaneous, and asynchronous neurotransmitter release. Importantly, our data demonstrate that Ca2+ binding by the C2A domain of synaptotagmin does not regulate asynchronous release and thus disprove the current inhibition hypothesis. We propose a spatial competition hypothesis to explain these seemingly discordant results of the differing C2A Ca2+ binding mutations.

scholarly journals RIM is essential for stimulated but not spontaneous somatodendritic dopamine release in the midbrain

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Brooks G Robinson ◽  
Xintong Cai ◽  
Jiexin Wang ◽  
James R Bunzow ◽  
John T Williams ◽  
...  
Keyword(s):  
Action Potentials ◽  
Dopamine Release ◽  
D2 Receptor ◽  
Dopamine Neurons ◽  
Molecular Scaffolds ◽  
Action Potential Firing ◽  
Neuron Morphology ◽  
Potential Firing ◽  
Molecular Machinery ◽  
Dopamine Signaling

Action potentials trigger neurotransmitter release at active zones, specialized release sites in axons. Many neurons also secrete neurotransmitters or neuromodulators from their somata and dendrites. However, it is unclear whether somatodendritic release employs specialized sites for release, and the molecular machinery for somatodendritic release is not understood. Here, we identify an essential role for the active zone protein RIM in stimulated somatodendritic dopamine release in the midbrain. In mice in which RIMs are selectively removed from dopamine neurons, action potentials failed to evoke significant somatodendritic release detected via D2 receptor-mediated currents. Compellingly, spontaneous dopamine release was normal upon RIM knockout. Dopamine neuron morphology, excitability, and dopamine release evoked by amphetamine, which reverses dopamine transporters, were also unaffected. We conclude that somatodendritic release employs molecular scaffolds to establish secretory sites for rapid dopamine signaling during firing. In contrast, basal release that is independent of action potential firing does not require RIM.

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