Slow‐decaying presynaptic calcium dynamics gate long‐lasting asynchronous release at the hippocampal mossy fiber to CA3 pyramidal cell synapse

Chamberland, Simon; Timofeeva, Yulia; Evstratova, Alesya; Norman, Christopher A.; Volynski, Kirill E.; Tóth, Katalin

doi:10.1002/syn.22178

Cited by 8 publications

(8 citation statements)

References 54 publications

(116 reference statements)

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“…To investigate the influence of aSN on the calcium concentration during an action potential spike train, we analyzed the mean calcium concentration during this process. In general, these simulations resulted in an oscillating increase of the calcium concentrations as observed in vitro (Chamberland et al , 2020) (Fig 6C). Figure 6D (lower right panel) shows the maximum of the mean calcium concentration during an action potential spike train (as visualized in Fig 6C).…”

Section: Resultssupporting

confidence: 68%

Monomeric α‐synuclein activates the plasma membrane calcium pump

Kowalski,

Betzer,

Larsen

et al. 2023

The EMBO Journal

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Alpha‐synuclein (aSN) is a membrane‐associated and intrinsically disordered protein, well known for pathological aggregation in neurodegeneration. However, the physiological function of aSN is disputed. Pull‐down experiments have pointed to plasma membrane Ca2+‐ATPase (PMCA) as a potential interaction partner. From proximity ligation assays, we find that aSN and PMCA colocalize at neuronal synapses, and we show that calcium expulsion is activated by aSN and PMCA. We further show that soluble, monomeric aSN activates PMCA at par with calmodulin, but independent of the autoinhibitory domain of PMCA, and highly dependent on acidic phospholipids and membrane‐anchoring properties of aSN. On PMCA, the key site is mapped to the acidic lipid‐binding site, located within a disordered PMCA‐specific loop connecting the cytosolic A domain and transmembrane segment 3. Our studies point toward a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.

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Section: Resultssupporting

confidence: 68%

Monomeric α‐synuclein activates the plasma membrane calcium pump

Kowalski,

Betzer,

Larsen

et al. 2023

The EMBO Journal

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“…3 , 5 Hz train) the global Ca 2+ signal is expected to build up several fold in comparison to that after a pair of action potentials (Fig. 4 ) 27 . In line with this, the asynchronous release fraction was ~3.5-fold higher during 5 Hz trains ( n A / n T ~ 0.25) than during paired-pulse recordings ( n A / n T ~ 0.07).…”

Section: Discussionmentioning

confidence: 94%

“…refs. 1 , 27 ). Nevertheless, consistent with our findings with the 5 Hz train, the asynchronous release fraction measured during the paired-pulse protocol was also elevated (~1.8-fold) in boutons with low release efficacy (T1, n T = 0.23 ± 0.02 and n A / n T = 0.10 ± 0.01) when compared to boutons with intermediate (T2, n T = 0.57 ± 0.05 and n A / n T = 0.06 ± 0.01) and high (T3, n T = 1.22 ± 0.07 and n A / n T = 0.05 ± 0.01) release efficacies (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For each active zone geometry, we simulated the action potential-evoked Ca 2+ influx and three-dimensional buffered diffusion and extrusion using the Virtual Cell (VCell) computational platform 37 , 38 (Methods and our previous work 27 , 39 – 41 ). In this way, we computed [Ca 2+ ] transients that occur at different locations in the active zone within the first 10 ms after an action potential.…”

Section: Resultsmentioning

confidence: 99%

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Asynchronous glutamate release is enhanced in low release efficacy synapses and dispersed across the active zone

et al. 2022

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The balance between fast synchronous and delayed asynchronous release of neurotransmitters has a major role in defining computational properties of neuronal synapses and regulation of neuronal network activity. However, how it is tuned at the single synapse level remains poorly understood. Here, using the fluorescent glutamate sensor SF-iGluSnFR, we image quantal vesicular release in tens to hundreds of individual synaptic outputs from single pyramidal cells with 4 millisecond temporal and 75 nm spatial resolution. We find that the ratio between synchronous and asynchronous synaptic vesicle exocytosis varies extensively among synapses supplied by the same axon, and that the synchronicity of release is reduced at low release probability synapses. We further demonstrate that asynchronous exocytosis sites are more widely distributed within the release area than synchronous sites. Together, our results reveal a universal relationship between the two major functional properties of synapses – the timing and the overall efficacy of neurotransmitter release.

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“…We previously constrained Ca 2+ dynamics at MFB release sites during high-frequency bursts of APs using a three-dimensional VCell model 27,28 . Here we used the previously estimated 5).…”

Section: Mixed Single and Dual Fusion Clamp Model Can Recapitulate Ve...mentioning

confidence: 99%

The release of inhibition model reproduces kinetics and plasticity of neurotransmitter release in central synapses

Norman

Krishnakumar

Timofeeva

et al. 2023

Preprint

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Calcium-evoked release of neurotransmitters from synaptic vesicles (SVs) is catalysed by SNARE proteins. The predominant view is that, at rest, complete assembly of SNARE complexes is inhibited (‘clamped’) by synaptotagmin and complexin molecules. Calcium binding by synaptotagmins releases this fusion clamp and triggers fast SV exocytosis. However, this model has not been quantitatively tested over physiological timescales. Here we describe an experimentally constrained computational modelling framework to quantitatively assess how the molecular architecture of the fusion clamp affects SV exocytosis. Our results argue that the “release-of-inhibition” model can indeed account for fast calcium-activated SV fusion, and that dual binding of synaptotagmin-1 and synaptotagmin-7 to the same SNARE complex enables synergistic regulation of the kinetics and plasticity of neurotransmitter release. The developed framework provides a powerful and adaptable tool to link the molecular biochemistry of presynaptic proteins to physiological data and efficiently test the plausibility of calcium-activated neurotransmitter release models.

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Slow‐decaying presynaptic calcium dynamics gate long‐lasting asynchronous release at the hippocampal mossy fiber to CA3 pyramidal cell synapse

Cited by 8 publications

References 54 publications

Monomeric α‐synuclein activates the plasma membrane calcium pump

Monomeric α‐synuclein activates the plasma membrane calcium pump

Asynchronous glutamate release is enhanced in low release efficacy synapses and dispersed across the active zone

The release of inhibition model reproduces kinetics and plasticity of neurotransmitter release in central synapses

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