Implication of synaptotagmins 4 and 7 in activity-dependent somatodendritic dopamine release in the ventral midbrain

Delignat-Lavaud, Benoît; Ducrot, Charles; Kouwenhoven, Willemieke M.; Feller, Nina; Trudeau, Louis-Éric

doi:10.1098/rsob.210339

Cited by 10 publications

(10 citation statements)

References 67 publications

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“…Prior work indicates that midbrain DA neurons express four Syt isoforms (1, 4, 7, and 11;Glavan and Zivin, 2005;Mendez et al, 2011;Delignat-Lavaud et al, 2022), of which Syt1 and Syt7 contain the Ca 21 -binding domains required to activate the SNARE complex and initiate transmitter release (Südhof, 2002). Here, we identified Syt1 protein in SNc DA neurons by immunostaining.…”

Section: Functional Substitution Of Syt1 For Syt7mentioning

confidence: 89%

“…7A). We and others have reported the apparent absence of detectable Syt1 immunoreactivity in midbrain DA neurons (Witkovsky et al, 2009;Delignat-Lavaud et al, 2022). Our earlier study (Witkovsky et al, 2009) used an Ab against Syt1,2 that did not stain guinea pig midbrain DA neurons.…”

Section: Calcium Dependence Of Somatodendritic Da Releasementioning

confidence: 90%

“…Moreover, the deletion of Syt1 in adrenal chromaffin cells leads to the loss of a fast release phase, leaving intact a slow release phase that is lost when Syt7 also is deleted (Schonn et al, 2008). Other Syts may play a role as well; for example, recent evidence indicates functional compensation by Syt4 in VTA DA neurons when Syt7 is deleted (Delignat-Lavaud et al, 2022). Overall, in DA neurons, the high affinity of Syt7 for Ca 21 coupled with a slow dissociation constant (Brandt et al, 2012) is well matched to the relatively slow kinetics of G-protein-activated DA receptors.…”

Section: Functional Substitution Of Syt1 For Syt7mentioning

confidence: 99%

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Synaptotagmins 1 and 7 Play Complementary Roles in Somatodendritic Dopamine Release

et al. 2022

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The molecular mechanisms underlying somatodendritic dopamine (DA) release remain unresolved, despite the passing of decades since its discovery. Our previous work showed robust release of somatodendritic DA in submillimolar extracellular Ca 21 concentration ([Ca 21 ] o ). Here we tested the hypothesis that the high-affinity Ca 21 sensor synaptotagmin 7 (Syt7), is a key determinant of somatodendritic DA release and its Ca 21 dependence. Somatodendritic DA release from SNc DA neurons was assessed using whole-cell recording in midbrain slices from male and female mice to monitor evoked DA-dependent D2 receptor-mediated inhibitory currents (D2ICs). Single-cell application of an antibody to Syt7 (Syt7 Ab) decreased pulse trainevoked D2ICs, revealing a functional role for Syt7. The assessment of the Ca 21 dependence of pulse train-evoked D2ICs confirmed robust DA release in submillimolar [Ca 21 ] o in wild-type (WT) neurons, but loss of this sensitivity with intracellular Syt7 Ab or in Syt7 knock-out (KO) mice. In millimolar [Ca 21 ] o , pulse train-evoked D2ICs in Syt7 KOs showed a greater reduction in decreased [Ca 21 ] o than seen in WT mice; the effect on single pulse-evoked DA release, however, did not differ between genotypes. Single-cell application of a Syt1 Ab had no effect on train-evoked D2ICs in WT SNc DA neurons, but did cause a decrease in D2IC amplitude in Syt7 KOs, indicating a functional substitution of Syt1 for Syt7. In addition, Syt1 Ab decreased single pulse-evoked D2ICs in WT cells, indicating the involvement of Syt1 in tonic DA release. Thus, Syt7 and Syt1 play complementary roles in somatodendritic DA release from SNc DA neurons.

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Section: Functional Substitution Of Syt1 For Syt7mentioning

confidence: 89%

Section: Calcium Dependence Of Somatodendritic Da Releasementioning

confidence: 90%

Section: Functional Substitution Of Syt1 For Syt7mentioning

confidence: 99%

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Synaptotagmins 1 and 7 Play Complementary Roles in Somatodendritic Dopamine Release

et al. 2022

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“…As a member of the synaptotagmin family, SYT4 is known to modulate membrane trafficking and act as a calcium signal sensor (.Bharat et al 2017 , Delignat-Lavaud et al 2022 ). It has been documented to regulate insulin granule positioning and pancreatic β-cell maturation (.Blum et al 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Amlodipine inhibits Synaptotagmin-4’s oncogenic activity on gastric cancer proliferation by targeting calcium signaling

Huang,

Yang,

Deng

et al. 2024

Funct Integr Genomics

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Background: Gastric cancer (GC) remains a leading cause of cancer mortality globally. Synaptotagmin-4 (SYT4), a calcium-sensing synaptic vesicle protein, has been implicated in the oncogenesis of diverse malignancies. Purpose: This study delineates the role of SYT4 in modulating clinical outcomes and biological behaviors in GC. Methods: We evaluated SYT4 expression in GC specimens using bioinformatics analyses and immunohistochemistry. Functional assays included CCK8 proliferation tests, apoptosis assays via flow cytometry, confocal calcium imaging, and xenograft models. Western blotting elucidated MAPK pathway involvement. Additionally, we investigated the impact of the calcium channel blocker amlodipine on cellular dynamics and MAPK pathway activity. Results: SYT4 was higher in GC tissues, and the elevated SYT4 was significantly correlated with adverse prognosis. Both univariate and multivariate analyses confirmed SYT4 as an independent prognostic indicator for GC. Functionally, SYT4 promoted tumorigenesis by fostering cellular proliferation, inhibiting apoptosis, and enhancing intracellular Ca2+ influx, predominantly via MAPK pathway activation. Amlodipine pre-treatment attenuated SYT4-driven cell growth and potentiated apoptosis, corroborated by in vivo xenograft assessments. These effects were attributed to MAPK pathway suppression by amlodipine. Conclusion: SYT4 emerges as a potential prognostic biomarker and a pro-oncogenic mediator in GC through a Ca2+-dependent MAPK mechanism. Amlodipine demonstrates significant antitumor effects against SYT4-driven GC, positing its therapeutic promise. This study underscores the imperative of targeting calcium signaling in GC treatment strategies.

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“…Syt7 RNA is expressed in many cell types in the brain but is enriched in SNc neurons ( Saunders et al, 2018 ). Studies using Syt7 KO animals or antibody-mediated inhibition suggest that SYT7 regulates dopamine release from the somatodendritic compartment ( Delignat-Lavaud et al, 2022 ; Hikima et al, 2022 ). Further, high-frequency stimulation restores somatodendritic dopamine release in SYT1 KO animals, and high-frequency stimulation and DAT blockade reveal a component of release from terminals in SYT1 KO animals that is postulated to be under the control of SYT7 ( Banerjee et al, 2020 ; Lebowitz et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Synaptotagmin-7 Counteracts Short-Term Depression during Phasic Dopamine Release

Lebowitz,

Kissiwaa,

Engeln

et al. 2024

eNeuro

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Dopamine neurons switch from tonic pacemaker activity to high-frequency bursts in response to salient stimuli. These bursts lead to superlinear increases in dopamine release, and the degree of this increase is highly dependent on firing frequency. The superlinearity and frequency-dependence of dopamine release implicates short-term plasticity processes. The presynaptic Ca2+-sensor synaptotagmin-7 (SYT7) has suitable properties to mediate such short-term plasticity and has been implicated in regulating dopamine release from somatodendritic compartments.Here we use a genetically-encoded dopamine sensor and whole-cell electrophysiology inSyt7knockout mice to determine how SYT7 contributes to both axonal and somatodendritic dopamine release. We find that SYT7 mediates a hidden component of facilitation of release from dopamine terminals that can be unmasked by lowering initial release probability, or by pre-depressing synapses with low-frequency stimulation. Depletion of SYT7 increased short-term depression and reduced release during stimulations that mimicin vivofiring. Recordings of D2-mediated inhibitory postsynaptic currents in the substantia nigra pars compacta (SNc) confirmed a similar role for SYT7 in somatodendritic release. Our results indicate that SYT7 drives short-term facilitation of dopamine release, which may explain the frequency-dependence of dopamine signaling seenin vivo.Significance StatementEach midbrain dopamine neuron releases onto thousands of downstream cells, allowing the activity of dopamine neurons to exert outsized impacts on movement, motivation, and learning. Dopamine release scales non-linearly with firing rates, suggesting these neurons might employ classical mechanisms of activity-dependent plasticity. Here we show that dopamine release sites in multiple brain regions employ a well-characterized mechanism for plasticity, synaptotagmin-7, to dramatically boost dopamine release during high-frequency activity. This work generalizes a mechanism of short term-plasticity that has been well-characterized at conventional synapses to the release of neuromodulators, and helps to explain the activity-dependence of dopamine release.

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Implication of synaptotagmins 4 and 7 in activity-dependent somatodendritic dopamine release in the ventral midbrain

Cited by 10 publications

References 67 publications

Synaptotagmins 1 and 7 Play Complementary Roles in Somatodendritic Dopamine Release

Synaptotagmins 1 and 7 Play Complementary Roles in Somatodendritic Dopamine Release

Amlodipine inhibits Synaptotagmin-4’s oncogenic activity on gastric cancer proliferation by targeting calcium signaling

Synaptotagmin-7 Counteracts Short-Term Depression during Phasic Dopamine Release

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