Tomosyn Inhibits Synaptic Vesicle Priming in Caenorhabditis elegans

Gracheva, Elena O.; Burdina, Anna O.; Holgado, Andrea; Berthelot-Grosjean, Martine; Ackley, Brian D.; Hadwiger, Gayla; Nonet, Michael L.; Weimer, Robby M.; Richmond, Janet E.

doi:10.1371/journal.pbio.0040261

Cited by 157 publications

(214 citation statements)

References 39 publications

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“…The prominent biophysical change observed at the fly NMJ after tomosyn RNAi is a prolonged EJC resulting in an increased total charge transfer, similar to that observed at C. elegans tomosyn mutant synapses (22,23). Although the underlying cause of the altered EJC duration in either C. elegans or Drosophila has yet to be determined, one potential explanation is the occurrence of late fusion events possibly resulting from ectopically primed vesicles distal to release sites.…”

Section: Discussionmentioning

confidence: 77%

Tomosyn-dependent regulation of synaptic transmission is required for a late phase of associative odor memory

Chen

Richlitzki

Featherstone

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic vesicle secretion requires the assembly of fusogenic SNARE complexes. Consequently proteins that regulate SNARE complex formation can significantly impact synaptic strength. The SNARE binding protein tomosyn has been shown to potently inhibit exocytosis by sequestering SNARE proteins in nonfusogenic complexes. The tomosyn–SNARE interaction is regulated by protein kinase A (PKA), an enzyme implicated in learning and memory, suggesting tomosyn could be an important effector in PKA-dependent synaptic plasticity. We tested this hypothesis in Drosophila , in which the role of the PKA pathway in associative learning has been well established. We first determined that panneuronal tomosyn knockdown by RNAi enhanced synaptic strength at the Drosophila larval neuromuscular junction, by increasing the evoked response duration. We next assayed memory performance 3 min (early memory) and 3 h (late memory) after aversive olfactory learning. Whereas early memory was unaffected by tomosyn knockdown, late memory was reduced by 50%. Late memory is a composite of stable and labile components. Further analysis determined that tomosyn was specifically required for the anesthesia-sensitive, labile component, previously shown to require cAMP signaling via PKA in mushroom bodies. Together these data indicate that tomosyn has a conserved role in the regulation of synaptic transmission and provide behavioral evidence that tomosyn is involved in a specific component of late associative memory.

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Section: Discussionmentioning

confidence: 77%

Tomosyn-dependent regulation of synaptic transmission is required for a late phase of associative odor memory

Chen

Richlitzki

Featherstone

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The slo-1 BK potassium channel gain-of-function allele ky399, which reduced ACh release (Davies et al 2003), was hypersensitive to fluoxetine in the paralysis assay (Figure 3d). Conversely, a slo-1 loss-of-function allele and a mutant of the negative ACh neurotransmission regulator tom-1 both exhibited an increase in ACh neurotransmission (Wang et al 2001;Gracheva et al 2006) and were both more resistant to fluoxetine as compared to WT (Figure 3d). These data suggest a model in which 5-HT signaling inhibits ACh neurotransmission and a deficit in ACh signaling may facilitate muscle relaxation following 5-HT and fluoxetine treatments.…”

Section: Resultsmentioning

confidence: 99%

A Genetic Survey of Fluoxetine Action on Synaptic Transmission in Caenorhabditis elegans

et al. 2010

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Fluoxetine is one of the most commonly prescribed medications for many behavioral and neurological disorders. Fluoxetine acts primarily as an inhibitor of the serotonin reuptake transporter (SERT) to block the removal of serotonin from the synaptic cleft, thereby enhancing serotonin signals. While the effects of fluoxetine on behavior are firmly established, debate is ongoing whether inhibition of serotonin reuptake is a sufficient explanation for its therapeutic action. Here, we provide evidence of two additional aspects of fluoxetine action through genetic analyses in Caenorhabditis elegans. We show that fluoxetine treatment and null mutation in the sole SERT gene mod-5 eliminate serotonin in specific neurons. These neurons do not synthesize serotonin but import extracellular serotonin via MOD-5/SERT. Furthermore, we show that fluoxetine acts independently of MOD-5/SERT to regulate discrete properties of acetylcholine (Ach), gamma-aminobutyric acid (GABA), and glutamate neurotransmission in the locomotory circuit. We identified that two G-protein-coupled 5-HT receptors, SER-7 and SER-5, antagonistically regulate the effects of fluoxetine and that fluoxetine binds to SER-7. Epistatic analyses suggest that SER-7 and SER-5 act upstream of AMPA receptor GLR-1 signaling. Our work provides genetic evidence that fluoxetine may influence neuronal functions and behavior by directly targeting serotonin receptors.

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“…6C) or decrease (unc-13/Munc13 or unc-18/Munc18) ( Fig. 7B; Supplemental Table S3) ACh secretion Weimer et al 2003;Madison et al 2005;Gracheva et al 2006;Vashlishan et al 2008;Hobson et al 2011;Martin et al 2011). In contrast, mutants expressing a constitutively active slo-1/BK potassium channel that inhibits neuronal activity (Richmond et al 2001;Q Liu et al 2007) displayed reduced SPHK-1-GFP punctal fluorescence (Fig.…”

Section: Endogenous Ach Regulates Sphk-1 Abundance At Synapsesmentioning

confidence: 95%

Recruitment of sphingosine kinase to presynaptic terminals by a conserved muscarinic signaling pathway promotes neurotransmitter release

Chan¹,

Hu²,

Sieburth³

2012

Genes Dev.

105

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Sphingolipids are potent lipid second messengers that regulate cell differentiation, migration, survival, and secretion, and alterations in sphingolipid signaling have been implicated in a variety of diseases. However, how sphingolipid levels are regulated, particularly in the nervous system, remains poorly understood. Here, we show that the generation of sphingosine-1-phosphate by sphingosine kinase (SphK) promotes neurotransmitter release. Electrophysiological, imaging, and behavioral analyses of Caenorhabditis elegans mutants lacking sphingosine kinase sphk-1 indicate that neuronal development is normal, but there is a significant defect in neurotransmitter release from neuromuscular junctions. SPHK-1 localizes to discrete, nonvesicular regions within presynaptic terminals, and this localization is critical for synaptic function. Muscarinic agonists cause a rapid increase in presynaptic SPHK-1 abundance, whereas reduction of endogenous acetylcholine production results in a rapid decrease in presynaptic SPHK-1 abundance. Muscarinic regulation of presynaptic SPHK-1 abundance is mediated by a conserved presynaptic signaling pathway composed of the muscarinic acetylcholine receptor GAR-3, the heterotrimeric G protein Gaq, and its effector, Trio RhoGEF. SPHK-1 activity is required for the effects of muscarinic signaling on synaptic transmission. This study shows that SPHK-1 promotes neurotransmitter release in vivo and identifies a novel muscarinic pathway that regulates SphK abundance at presynaptic terminals.

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Tomosyn Inhibits Synaptic Vesicle Priming in Caenorhabditis elegans

Cited by 157 publications

References 39 publications

Tomosyn-dependent regulation of synaptic transmission is required for a late phase of associative odor memory

Tomosyn-dependent regulation of synaptic transmission is required for a late phase of associative odor memory

A Genetic Survey of Fluoxetine Action on Synaptic Transmission in Caenorhabditis elegans

Recruitment of sphingosine kinase to presynaptic terminals by a conserved muscarinic signaling pathway promotes neurotransmitter release

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