Synaptotagmin-1 is a Ca2+ sensor for somatodendritic dopamine release

Lebowitz, Joseph J.; Banerjee, Aditi; Qiao, Claire; Bunzow, James R.; Williams, John T.; Kaeser, Pascal S.

doi:10.1016/j.celrep.2022.111915

Cited by 8 publications

(11 citation statements)

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“…Despite this shared necessity of RIM, dendrites and terminals may employ different Ca 2+ sensors for release. The vesicular Ca 2+ sensor SYT1 is required for release from terminals ( Banerjee et al, 2020 ), but there are mixed results regarding its necessity for release from somatodendritic compartments ( Delignat-Lavaud et al, 2021 ; Lebowitz et al, 2023 ). Variable results have also been observed for SYT7's role in the somatodendritic compartment.…”

Section: Discussionmentioning

confidence: 99%

“…Acute SNc slices were prepared from P30 to 70 mice as previously described ( Robinson et al, 2019 ; Lebowitz et al, 2023 ). Animals were anesthetized with isoflurane before rapid decapitation into warmed (∼35°C) Krebs buffer containing (in mM) 126 NaCl, 1.2 MgCl 2 , 2.4 CaCl 2 , 1.4 NaH 2 PO 4 , 25 NaHCO 3 , and 11 dextrose.…”

Section: Methodsmentioning

confidence: 99%

“…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 ). However, direct observation of SYT7-mediated short-term plasticity from dopamine terminals is lacking.…”

Section: Introductionmentioning

confidence: 91%

“…At most presynaptic terminals, including those of dopamine neurons, action potential-induced Ca 2+ influx triggers fast synchronous fusion by activating the low-affinity vesicular Ca 2+ sensor synaptotagmin-1 (SYT1; Banerjee et al, 2020 ; Hikima et al, 2022 ; Liu et al, 2022 ; Delignat-Lavaud et al, 2023 ; Lebowitz et al, 2023 ). After Ca 2+ influx, submicromolar “residual” Ca 2+ persists in the presynaptic cytoplasm for hundreds of milliseconds and activates the high-affinity Ca 2+ sensor synaptotagmin-7 (SYT7).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Lebowitz,

Kissiwaa,

Engeln

et al. 2024

eNeuro

Self Cite

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“…Here, the burst transition is induced by the enlargement of the positive feedback loop between Ca and I CAN . Experimentally, somatodendritic [48] and axonal [49] December 27, 2023 15/21 synchronous DA release relies on large-scale high-intensity calcium oscillations and fast Ca 2+ sensor synaptotagmin-1. Besides of I N M DA , calcium from other sources also contribute to Ca accumulation, such as voltage gated calcium channels (VGCCs) [50] , nACh receptors [51], and intracellular calcium stores [52].…”

Section: Discussionmentioning

confidence: 99%

Dynamics of burst synchronization induced by excitatory inputs on midbrain dopamine neurons

Chen

2023

Preprint

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Dopamine (DA) signals play critical roles in reward-related behavior, decision making, and learning. Yet the mainstream notion that DA signals are encoded by the temporal dynamics of individual DA cell activity is increasingly contested with data supporting that DA signals prefer to be encoded by the spatial organization of DA neuron populations. However, how distributed and parallel excitatory afferent inputs simultaneously induce burst synchronization (BS) is unclear. Our previous work implies that the burst could presumably transition from an integrator to a resonator if the excitatory inputs increase further. Here the responses of networked DA neurons to different intensity of excitatory inputs are investigated. It is found that as NMDA conductance increases, the network will transition from resting state to burst asynchronization (BA) state and then to BS state, showing a bounded BA and BS region in the NMDA conductance space. Furthermore, it is found that as muscarinic receptors modulatedCa2+dependent cationic (CAN) conductance increases, both boundaries between resting and BA, and between BA and BS gradually decrease. Phase plane analysis on DA reduced model unveils that the burst transition to a resonator underpins the changes in the network dynamics. Slow-fast dissection analysis on DA full model uncovers that the underlying mechanism of the roles and synergy of NMDA and muscarinic receptors in inducing the burst transition emerge from the enlargement of nonlinear positive feedback relationship between moreCa2+influx provided by additional NMDA current and moreICANmodulated by added muscarinic receptors. Moreover, the lag in DA volume transmission has no effect on excitatory inputs-elicited resonator BS except for requiring more excitatory inputs. These findings shed new lights on understanding the collective behavior of DA cells population regulated by the distributed excitatory inputs, and might provide a new perspective for understanding the abnormal DA release in pathological states.Author summaryThe importance of DA signals is beyond doubt, so their encoding mechanism has very important biological significance and draws widespread attention. Yet the mainstream notion that DA cells individual provide a uniform, broadly distributed signal is increasingly contested with data supporting both homogeneity across dopamine cell activity and diversity in DA signals in target regions. Our article proposes that diverse distributed and parallel excitatory inputs can not only regulate the temporal dynamics of individual DA cell activity, but also simultaneously and synergistically regulate the network dynamics of DA cell populations by changing the local dynamics of DA cells, namely the burst transition from integrators to resonators. According to our perspective, many data that are difficult to interpret by the notion of the DA neuron individual coding can be well explained, such as burst asynchronization coding DA ramping signals, the scale of burst synchronization coding the amplitude of phase DA release, inhibitory DA autoreceptors facilitating resonator burst synchronization by postinhibitory rebound, etc. This study aims to elucidate the working mechanism of the DA system in physiological states such as positive reinforcement, and then to provide a new research perspective and foundation for understanding the abnormal DA release in pathological states.

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Unraveling the Potential of EphA4: A Breakthrough Target and Beacon of Hope for Neurological Diseases

2023

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Synaptotagmin-1 is a Ca2+ sensor for somatodendritic dopamine release

Cited by 8 publications

References 84 publications

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

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

Dynamics of burst synchronization induced by excitatory inputs on midbrain dopamine neurons

Unraveling the Potential of EphA4: A Breakthrough Target and Beacon of Hope for Neurological Diseases

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