Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses

Liu, Haowen; Li, Lei; Wang, Wei; Gong, Jihong; Yang, Xiaofei; Hu, Zhitao

doi:10.1016/j.celrep.2018.02.023

Cited by 36 publications

(61 citation statements)

References 43 publications

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“…We next examined the functional roles of the C2A/C2A homodimerization and C2A/RIM heterodimerization in tonic neurotransmitter release by measuring miniature excitatory/inhibitory postsynaptic currents (mEPSCs/mIPSCs) at the neuromuscular junction. Both the mEPSCs and the mIPSCs were recorded in the presence of 0mM and 1mM Ca 2+ , as we have previously found that the mIPSCs are nearly arrested in 0mM Ca 2+ but are normal 1mM Ca 2+ in some mutants (Liu et al, 2018), suggesting that different Ca 2+ concentrations should be tested to provide an accurate and thorough evaluation of tonic release. Our results showed that the mEPSCs and mIPSCs were completely abolished in the unc-13(s69) null mutant, and were fully restored by neuronal expression of full-length UNC-13L ( Figure 2).…”

Section: Disrupting C2a/rim Heterodimerization Reduces Mepscs/mipscs mentioning

confidence: 99%

“…Thus, the UNC-13L C2A domain is important for tonic release of both ACh and GABA; however, the requirement for C2A in GABA release can be bypassed by the presence of extracellular calcium, presumably due to increased release probability. The differential impact of deleting C2A on ACh and GABA release in 1mM Ca 2+ could reflect differences in release probability at these two types of synapses (Liu et al, 2018). In fact, SV release from inhibitory synapses displays a higher release probability than excitatory synapses in the mammalian central nervous system (Zhou et al, 2013b;Zhou et al, 2013c).…”

Section: Disrupting C2a/rim Heterodimerization Reduces Mepscs/mipscs mentioning

confidence: 99%

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Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming

Nedelcu

et al. 2018

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UNC-13 proteins play an essential role in synaptic transmission by recruiting synaptic vesicles (SVs) to become available for release, which is termed SV priming. Here we show that the C2A domain of UNC-13L, like the corresponding domain in mammalian Munc13-1, displays two conserved binding modes: forming C2A/C2A homodimers, or forming a heterodimer with the zinc finger domain of UNC-10/RIM (C2A/RIM). Functional analysis revealed that UNC-13L's C2A promotes synaptic transmission by regulating a post-priming process. Stimulus-evoked release but not SV priming, was impaired in unc-10 mutants deficient for C2A/RIM heterodimerization, leading to decreased release probability. Disrupting C2A/C2A homodimerization in UNC-13L-rescued animals had no effect on synaptic transmission, but fully restored the evoked release and the release probability of unc-10/RIM mutants deficient for C2A/RIM heterodimerization. Thus, our results support the model that RIM binding C2A releases UNC-13L from an autoinhibitory

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Section: Disrupting C2a/rim Heterodimerization Reduces Mepscs/mipscs mentioning

confidence: 99%

Section: Disrupting C2a/rim Heterodimerization Reduces Mepscs/mipscs mentioning

confidence: 99%

Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming

Nedelcu

et al. 2018

Preprint

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“…Over 15 synaptotagmin isoforms have been identified in mammals, several of which have been shown to be important for synaptic vesicle (SV) exocytosis (Brose et al, 1992;Xu et al, 2007;Weber et al, 2014). Synaptotagmin-1 (Syt1), one of the most important members of the family, has been demonstrated to act as the major Ca 2ϩ sensor of neurotransmitter release at many types of synapses (Geppert et al, 1994;Yoshihara and Littleton, 2002;Lee et al, 2013;. Each C2 domain of Syt1 contains five Ca 2ϩ -binding residues (aspartates; Nishiki and Augustine, 2004a).…”

Section: Introductionmentioning

confidence: 99%

SNT-1 Functions as the Ca²⁺ Sensor for Tonic and Evoked Neurotransmitter Release in Caenorhabditis Elegans

Li¹,

Liu²,

Wang³

et al. 2018

J. Neurosci.

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Synaptotagmin-1 (Syt1) binds Ca through its tandem C2 domains (C2A and C2B) and triggers Ca-dependent neurotransmitter release. Here, we show that , the homolog of mammalian Syt1, functions as the Ca sensor for both tonic and evoked neurotransmitter release at the neuromuscular junction. Mutations that disrupt Ca binding in double C2 domains of SNT-1 significantly impaired tonic release, whereas disrupting Ca binding in a single C2 domain had no effect, indicating that the Ca binding of the two C2 domains is functionally redundant for tonic release. Stimulus-evoked release was significantly reduced in mutants, with prolonged release latency as well as faster rise and decay kinetics. Unlike tonic release, evoked release was triggered by Ca binding solely to the C2B domain. Moreover, we showed that SNT-1 plays an essential role in the priming process in different subpopulations of synaptic vesicles with tight or loose coupling to Ca entry. We showed that SNT-1 in regulates evoked neurotransmitter release through Ca binding to its C2B domain in a similar way to Syt1 in the mouse CNS and the fly neuromuscular junction. However, the largely decreased tonic release in mutants argues SNT-1 has a clamping function. Indeed, Ca-binding mutations in the C2 domains in SNT-1 significantly reduced the frequency of the miniature EPSC, indicating that SNT-1 also acts as a Ca sensor for tonic release. Therefore, revealing the differential mechanisms between invertebrates and vertebrates will provide significant insights into our understanding how synaptic vesicle fusion is regulated.

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“…An unc-2 gain-of-function mutation results in E/I imbalance Presynaptic Ca 2+ influx through CaV2 channels is tightly coupled to neurotransmitter release. In accordance, unc-2 loss-of-function mutants are resistant to the acetylcholinesterase inhibitor aldicarb (Miller et al, 1996), and have a reduction in spontaneous EPSC frequency (Richmond et al, 2001;Tong et al, 2015;Liu et al, 2018). The unc-2(gf) mutation increases Ca 2+ influx, which would lead to an increase in neurotransmitter release probability.…”

Section: Discussionmentioning

confidence: 91%

Gain-of-function mutations in the UNC-2/CaV2α channel lead to hyperactivity and excitation-dominant synaptic transmission in Caenorhabditis elegans

Huang

Rayes

et al. 2019

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Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(gf) mutants unc-2(gf) mutants display increased cholinergicand decreased GABAergic-transmission. Moreover, we reveal that and increased cholinergic transmission in unc-2(gf) mutants leads to reduction of GABA synapses in a TAX-6/calcineurin dependent manner. Our studies provide mechanistic insight into how CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system. IntroductionMaintenance of proper brain function requires the balance of excitatory and inhibitory synaptic transmission. There is an increasing amount of evidence that the disruption of E/I balance in neural circuits is associated with neurological disorders, including autism, epilepsy and migraine (Nelson and Valakh, 2015;Vecchia and Pietrobon, 2012). Several studies have proposed that impaired inhibitory function may drive a shift in E/I balance towards excitation, and underlie the phenotypic changes observed in these disorders (Selten et al., 2018;Mainero and Louapre, 2014). While animal model studies provide support for this hypothesis, our understanding of the molecular and cellular mechanisms that lead to E/I imbalance remains limited.Mutations in the CACNA1A gene, which encodes the pore-forming α subunit of the CaV2.1 (P/Q type) voltage-gated calcium channel (VGCC), are associated with a broad spectrum of autosomal dominant neurological disorders. CaV2 VGCCs are the predominant channels in presynaptic nerve terminals, where they mediate the Ca 2+ influx that triggers the fusion of synaptic vesicles with the presynaptic membrane (Catterall, 2000;Bidaud et al., 2006). CACNA1A mutations can cause episodic ataxia type 2 (EA2), epileptic seizures and familial hemiplegic migraine type 1 (FHM1) (Pietrobon, 2010). Episodic ataxia type 2 (EA2), whose clinical features include the lack of voluntary coordination of muscle movements and epileptic seizures, is associated with a range of missense, nonsense-, and 3 splice site mutations throughout the CACNA1A gene. Familial hemiplegic migraine type 1 (FHM1), a severe variant of migraine that can co-occur with tonic-clonic seizures, has been found to be associated with missense mutations near the voltage sensors of the α1 subunit (Adams and Snutch, 2007).Electrophysiological analyses suggest that EA2 mutations lead to diminished channel functions, whereas both gain-and loss-of-channel function p...

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Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses

Cited by 36 publications

References 43 publications

Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming

Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming

SNT-1 Functions as the Ca²⁺ Sensor for Tonic and Evoked Neurotransmitter Release in Caenorhabditis Elegans

Gain-of-function mutations in the UNC-2/CaV2α channel lead to hyperactivity and excitation-dominant synaptic transmission in Caenorhabditis elegans

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Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses

Cited by 36 publications

References 43 publications

Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming

Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming

SNT-1 Functions as the Ca2+ Sensor for Tonic and Evoked Neurotransmitter Release in Caenorhabditis Elegans

Gain-of-function mutations in the UNC-2/CaV2α channel lead to hyperactivity and excitation-dominant synaptic transmission in Caenorhabditis elegans

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SNT-1 Functions as the Ca²⁺ Sensor for Tonic and Evoked Neurotransmitter Release in Caenorhabditis Elegans