The Munc13 proteins differentially regulate readily releasable pool dynamics and calcium-dependent recovery at a central synapse
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The Munc13 gene family encodes molecules located at the synaptic active zone that regulate the reliability of synapses to encode information over a wide range of frequencies in response to action potentials. In the CNS, proteins of the Munc13 family are critical in regulating neurotransmitter release and synaptic plasticity. Although Munc13-1 is essential for synaptic transmission, it is paradoxical that Munc13-2 and Munc13-3 are functionally dispensable at some synapses, although their loss in other synapses leads to increases in frequency-dependent facilitation. We addressed this issue at the calyx of Held synapse, a giant glutamatergic synapse that we found to express all these Munc13 isoforms. We studied their roles in the regulation of synaptic transmission and their impact on the reliability of information transfer. Through detailed electrophysiological analyses of Munc13-2, Munc13-3, and Munc13-2-3 knock-out and wild-type mice, we report that the combined loss of Munc13-2 and Munc13-3 led to an increase in the rate of calcium-dependent recovery and a change in kinetics of release of the readily releasable pool. Furthermore, viral-mediated overexpression of a dominant-negative form of Munc13-1 at the calyx demonstrated that these effects are Munc13-1 dependent. Quantitative immunohistochemistry using Munc13–fluorescent protein knock-in mice revealed that Munc13-1 is the most highly expressed Munc13 isoform at the calyx and the only one highly colocalized with Bassoon at the active zone. Based on these data, we conclude that Munc13-2 and Munc13-3 isoforms limit the ability of Munc13-1 to regulate calcium-dependent replenishment of readily releasable pool and slow pool to fast pool conversion in central synapses.
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Munc13-1/2 are putative markers of primed vesicles.
“and Munc13-1/2, putative markers of primed vesicles [14,42–45,60,61].”
From Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons (2024) · cites this paper as [60]
The Introduction (page not supplied) describes Munc13 proteins as regulators of vesicle priming, and the section on subsynaptic distributions reports Munc13-1 and Munc13-2 signals at presynaptic sites. The paper does not establish that either protein specifically marks vesicles that are already primed. (LLM, conf=0.83)
Experimental — accuracy not yet measuredBassoon strongly colocalizes with Munc13-1 but not Munc13-2 at AZs.
“Bassoon, a scaffold protein, is another candidate for phosphorylation, as it strongly colocalizes with Munc13-1 but not Munc13-2 at AZs [60].”
From Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons (2024) · cites this paper as [60]
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Recent advances in understanding the genetics of sleep
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NLP-12 Engages Different UNC-13 Proteins to Potentiate Tonic and Evoked Release
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The role of snare proteins in cortical development
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Helper-Dependent Adenoviral Vectors and Their Use for Neuroscience Applications
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Presynaptic GCaMP expression decreases vesicle release probability at the calyx of Held
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“To probe the Ca 2+ channel–sensor coupling topography, we targeted Ca V 2.1, the major type of presynaptic Ca 2+ channel in MFBs [58,59] and Munc13-1/2, putative markers of primed vesicles [14,42–45,60 ,61 ].”
InfluentialSynaptic Effects of Munc18-1 Alternative Splicing in Excitatory Hippocampal Neurons
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Munc13 Is a Molecular Target of Bryostatin 1
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The M domain in UNC-13 regulates the probability of neurotransmitter release
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Munc13-4 mediates tumor immune evasion by regulating the sorting and secretion of PD-L1 via exosomes
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SNARE Complex–Associated Proteins and Alcohol
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Resveratrol inhibits phorbol ester-induced membrane translocation of presynaptic Munc13-1
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Macromolecular complexes at active zones: integrated nano-machineries for neurotransmitter release
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Effect of ethanol on Munc13‐1 C1 in Membrane: A Molecular Dynamics Simulation Study
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Self-citationCritical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation
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Presynaptic mitochondria volume and abundance increase during development of a high-fidelity synapsePreprint
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Presynaptic α2δs specify synaptic gain, not synaptogenesis, in the mammalian brain
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Self-citationProbing the Diacylglycerol Binding Site of Presynaptic Munc13-1
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- Authors
- Chen, Z., Cooper, B., Kalla, S., Varoqueaux, F., & Young, S. M.
- Affiliations
- Max Planck Florida Institute for Neuroscience (US)
- Max Planck Institute of Experimental Medicine (DE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-05-08
- Volume
- 33
- Issue
- 19
- Pages
- 8336-8351
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6619620
- OpenAlex
- W2079607057
- Cited by
- 102
- References
- 55
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 10 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 12 · 2017: 11 · 2016: 5 · 2015: 10 · 2014: 7 · 2013: 3
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- IRIS (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Munc13, Munc13-1, readily releasable pool, calyx of Held, synaptic transmission, synaptic reliability, glutamatergic synapses, active zone, bassoon, knockout mice
- MeSH terms
- Age Factors, Analysis of Variance, Animals, Animals, Newborn, Brain Stem, Calcium, Electric Stimulation, Female, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Synaptic Transmission, Synapses, Mice, Knockout, Patch-Clamp Techniques, Gene Expression Regulation, Developmental, Excitatory Postsynaptic Potentials, Intracellular Signaling Peptides and Proteins, Green Fluorescent Proteins, Vesicular Glutamate Transport Protein 1, Mice, In Vitro Techniques
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