Characterization of developmental and molecular factors underlying release heterogeneity at Drosophila synapses

Akbergenova, Yulia; Cunningham, Karen L; Zhang, Yao V; Weiss, Shirley; Littleton, J Troy

doi:10.7554/elife.38268

Cited by 100 publications

(172 citation statements)

References 123 publications

(259 reference statements)

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“…This phenotype was never observed in controls 496 (average protrusions per MN1-Ib NMJ: UAS-TeTXLC: 0, n=14; MN1-Ib GAL4: 0, n=25; MN1-497 Ib>TeTXLC: 7.2 ± 2.4, n=16, F (4, 83) = 9.921, p=0.0001, Figure 11D). Similar filopodial-like 498 protrusions were described previously at early 1 st instar NMJs during the initial stages of synapse 499 formation in wildtype animals, but never at mature 3 rd instar NMJs (Akbergenova et al, 2018). 500 Such protrusions were not observed in silenced Is motoneurons or in Ib motoneurons following Is 501 silencing ( Figure 11A-D), indicating MN1-Ib and MNIs react differently to changes in their own 502 activity.…”

Section: Ib Ablation Resulted In M1 Having No Synaptic Innervation (4supporting

confidence: 69%

“…We and others have observed similar filopodial-like extensions at newly forming NMJ 569 connections in late embryos and early 1 st instar larvae (Halpern et al, 1991;Broadie and Bate, 570 1993;Ritzenthaler et al, 2000;Ritzenthaler and Chiba, 2003;Kohsaka and Nose, 2009;571 Akbergenova et al, 2018). These presynaptic filopodial processes contain elevated levels of the 572 Cacophony (Cac) N-type Ca 2+ channel and interact with GluRIIA-rich myopodia, with some 573 progressing to form new synapses during early development (Akbergenova et al, 2018). Due to 574 the lack of reinforcement signals caused by absence of synaptic activity in silenced MN1-Ib 575 motoneurons, we hypothesize these processes fail to properly drive AZ assembly and new synapse 576 formation.…”

Section: Ib Ablation Resulted In M1 Having No Synaptic Innervation (4mentioning

confidence: 99%

“…Live imaging was done under desflurane anesthesia at muscles M1 and M4 at abdominal segments 160 A2-A4 as previously described (Akbergenova et al, 2018). Selected larvae were covered with 161 halocarbon oil and a cover glass and imaged.…”

Section: Live Imaging Of Ib and Is Innervation And Synaptic Growth 159mentioning

confidence: 99%

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Synaptic plasticity induced by differential manipulation of tonic and phasic motoneurons in Drosophila

Aponte-Santiago

Ormerod

Akbergenova

et al. 2020

Preprint

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18Structural and functional plasticity induced by neuronal competition is a common feature of 19 developing nervous systems. However, the rules governing how postsynaptic cells differentiate 20 between presynaptic inputs are unclear. In this study we characterized synaptic interactions 21 following manipulations of Ib tonic or Is phasic glutamatergic motoneurons that co-innervate 22 Significance Statement 41Both invertebrate and vertebrate nervous systems display synaptic plasticity in response to 42 behavioral experiences, indicating underlying mechanisms emerged early in evolution. How 43 specific neuronal classes innervating the same postsynaptic target display distinct types of 44 plasticity is unclear. Here, we examined if Drosophila tonic Ib and phasic Is motoneurons display 45 competitive or cooperative interactions during innervation of the same muscle, or compensatory 46 changes when the output of one motoneuron is altered. We established a system to differentially 47 manipulate the motoneurons and examined the effects of cell-type specific changes to one of the 48 inputs. Our findings indicate Ib and Is motoneurons respond differently to activity mismatch or 49 loss of the co-innervating input, with the tonic subclass responding robustly compared to phasic 50 motoneurons. 51 52 6

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Section: Ib Ablation Resulted In M1 Having No Synaptic Innervation (4supporting

confidence: 69%

Section: Ib Ablation Resulted In M1 Having No Synaptic Innervation (4mentioning

confidence: 99%

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Synaptic plasticity induced by differential manipulation of tonic and phasic motoneurons in Drosophila

Aponte-Santiago

Ormerod

Akbergenova

et al. 2020

Preprint

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“…Several studies have shown that presynaptic release positively correlates with AZ-size 3, 42-45 . Therefore, we expected that the increase of AZ-BRP/Unc13A observed upon PhTx treatment would functionally increase presynaptic release (Fig.…”

Section: Resultsmentioning

confidence: 99%

Rapid active zone remodeling consolidates presynaptic potentiation

Boehme

McCarthy

Grasskamp

et al. 2018

Preprint

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1 Synaptic transmission is mediated by neurotransmitter release at presynaptic active zones (AZs) 2 followed by postsynaptic neurotransmitter detection. Plastic changes in transmission maintain 3 functionality during perturbations and enable memory formation. Postsynaptic plasticity targets 4 neurotransmitter receptors, but presynaptic plasticity mechanisms directly regulating the 5 neurotransmitter release apparatus remain largely enigmatic. Here we describe that AZs consist 6 of nano-modular release site units and identify a molecular sequence adding more modules 7 within minutes of plasticity induction. This requires cognate transport machinery and a discrete 8 subset of AZ scaffold proteins. Structural remodeling is not required for the immediate 9 potentiation of neurotransmitter release, but rather necessary to sustain this potentiation over 10 longer timescales. Finally, mutations in Unc13 that disrupt homeostatic plasticity at the 11 neuromuscular junction also impair shot-term memory when central neurons are targeted, 12 suggesting that both forms of plasticity operate via Unc13. Together, while immediate synaptic 13 potentiation capitalizes on available material, it triggers the coincident incorporation of modular 14 release sites to consolidate stable synapse function. 16Neurotransmitter-laden synaptic vesicles (SVs) release their content at presynaptic active zones 17 (AZs) in response to Ca 2+ influx through voltage gated channels that respond to action-potential 18 (AP) depolarization. Neurotransmitter binding to postsynaptic receptors subsequently leads to 19 their activation for synaptic transmission. Modulation of transmission strength is called synaptic 20 plasticity. Long-term forms of synaptic plasticity are major cellular substrates for learning, 21 memory, and behavioral adaptation 1, 2 . Mechanisms of long-term synaptic plasticity modify the 22 structure and function of the presynaptic terminal and/or the postsynaptic apparatus. AZs are 23 covered by complex scaffolds composed of a conserved set of extended structural proteins. 24 ELKS/Bruchpilot (BRP), RIM, and RIM-binding protein (RBP) functionally organize the 25 coupling between Ca 2+ -channels and release machinery by immobilizing the critical (M)Unc13 26 release factors in clusters close to presynaptic Ca 2+ -channels and thus generate SV release sites, 27 at both mammalian and Drosophila synapses 3-12 . Whether and how discrete AZ release sites and 28 the associated release machinery are reorganized during plastic changes remains unknown. 29 One crucial form of presynaptic plasticity is the homeostatic control of neurotransmitter 30 release. This process, referred to as presynaptic homeostatic potentiation (PHP), is observed in 31 organisms ranging from invertebrates to humans, but is perhaps best illustrated at the larval 32 neuromuscular junction (NMJ) of Drosophila melanogaster 13, 14 . Here, PHP requires the core 33 AZ-scaffolding proteins RIM, RBP and Fife 15-17 and physiologically coincides with the 34 upregulat...

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“…Membrane‐delimited ApSrc‐gCAMPS6 was made first by cutting out the sequence encoding GCaMP6f () with Bgl II and Not I and inserting into the compatible sites BamHI and EagI in the pNEX3 vector to generate pNEX3‐GCaMP6f. Similar to previous membrane‐delimited GCaMPs (Shigetomi et al ; Akbergenova et al ), we used the first 34 amino acids of Aplysia Src (NP_001191639.1) containing putative myristoylation and palmitoylation sites inserted in front of the GCaMP sequence. The sequence was purchased as a gBLOCK (IDT) with HinDIII and XbaI sites and inserted into pNEX3‐GCaMP6f at the same sites.…”

Section: Methodsmentioning

confidence: 99%

A role for Numb in Protein kinase M (PKM)‐mediated increase in surface AMPA receptors during facilitation in Aplysia

Farah

Dunn

Hastings

et al. 2019

Journal of Neurochemistry

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There is considerable evidence from both vertebrates and invertebrates that persistently active protein kinases maintain changes in synaptic strength that underlie memory. In the hermaphrodite marine mollusk, Aplysia californica, truncated forms of protein kinase C (PKC) termed protein kinase Ms have been implicated in both intermediate‐ and long‐term facilitation, an increase in synaptic strength between sensory neurons and motor neurons thought to underlie behavioural sensitization in the animal. However, few substrates have been identified as candidates that could mediate this increase in synaptic strength. PKMs have been proposed to maintain synaptic strength through preventing endocytosis of AMPA receptors. Numb is a conserved regulator of endocytosis that is modulated by phosphorylation. We have identified and cloned Aplysia Numb (ApNumb). ApNumb contains three conserved PKC phosphorylation sites and PKMs generated from classical and atypical Aplysia PKCs can phosphorylate ApNumb in vitro and in cells. Over‐expression of ApNumb that lacks the conserved PKC phosphorylation sites blocks increases in surface levels of a pHluorin‐tagged Aplysia glutamate receptor measured using live imaging after intermediate‐ or long‐term facilitation. Over‐expression of this form of ApNumb did not block increases in synaptic strength seen during intermediate‐term facilitation, but did block increases in synaptic strength seen during long‐term facilitation. There was no effect of over‐expression of this form of ApNumb on other putative Numb targets as measured using increases in calcium downstream of neurotrophins or agonists of metabotropic glutamate receptors. These results suggest that in Aplysia neurons, Numb specifically regulates AMPA receptor trafficking and is an attractive candidate for a target of PKMs in long‐term maintenance of synaptic strength. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/

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Characterization of developmental and molecular factors underlying release heterogeneity at Drosophila synapses

Cited by 100 publications

References 123 publications

Synaptic plasticity induced by differential manipulation of tonic and phasic motoneurons in Drosophila

Synaptic plasticity induced by differential manipulation of tonic and phasic motoneurons in Drosophila

Rapid active zone remodeling consolidates presynaptic potentiation

A role for Numb in Protein kinase M (PKM)‐mediated increase in surface AMPA receptors during facilitation in Aplysia

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