Glutamate Receptors in Synaptic Assembly and Plasticity: Case Studies on Fly NMJs

Thomas, Ulrike; Sigrist, Stephan J.

doi:10.1007/978-3-7091-0932-8_1

Cited by 22 publications

(22 citation statements)

References 169 publications

(201 reference statements)

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“…Larger T-Bars and synaptic vesicles at PM-Neto-rescued NMJs may reflect a homeostatic compensatory response to reduced postsynaptic receptors. Similar structures were reported in mutants with enhanced presynaptic release [10]. …”

Section: Resultssupporting

confidence: 82%

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Prodomain Removal Enables Neto to Stabilize Glutamate Receptors at the Drosophila Neuromuscular Junction

et al. 2015

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Stabilization of neurotransmitter receptors at postsynaptic specializations is a key step in the assembly of functional synapses. Drosophila Neto (Neuropillin and Tolloid-like protein) is an essential auxiliary subunit of ionotropic glutamate receptor (iGluR) complexes required for the iGluRs clustering at the neuromuscular junction (NMJ). Here we show that optimal levels of Neto are crucial for stabilization of iGluRs at synaptic sites and proper NMJ development. Genetic manipulations of Neto levels shifted iGluRs distribution to extrajunctional locations. Perturbations in Neto levels also produced small NMJs with reduced synaptic transmission, but only Neto-depleted NMJs showed diminished postsynaptic components. Drosophila Neto contains an inhibitory prodomain that is processed by Furin1-mediated limited proteolysis. neto null mutants rescued with a Neto variant that cannot be processed have severely impaired NMJs and reduced iGluRs synaptic clusters. Unprocessed Neto retains the ability to engage iGluRs in vivo and to form complexes with normal synaptic transmission. However, Neto prodomain must be removed to enable iGluRs synaptic stabilization and proper postsynaptic differentiation.

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Section: Resultssupporting

confidence: 82%

“…The fly NMJ is a glutamatergic synapse similar in composition and physiology to vertebrate AMPA/kainate central synapses [10,11]. The fly NMJ iGluRs are tetrameric complexes composed of three essential subunits, GluRIIC, GluRIID and GluRIIE, absolutely required for assembling functional channels [12–14].…”

Section: Introductionmentioning

confidence: 99%

Prodomain Removal Enables Neto to Stabilize Glutamate Receptors at the Drosophila Neuromuscular Junction

et al. 2015

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“…An alternative hypothesis is that Mgat1 phenotypes may result from the presence of high-mannose glycans on sites normally carrying complex/hybrid structures (Schachter, 2010), suggesting possible gain of function rather than loss of function of specific N-glycan classes. NMJ branch and bouton number play roles in determining functional strength (Thomas and Sigrist, 2012), although active zones and GluRs are also regulated independently (DiAntonio, 2006). Thus, the increased functional strength could be caused by increased structure at Mgat1 null NMJs.…”

Section: Discussionmentioning

confidence: 99%

N-glycosylation requirements in neuromuscular synaptogenesis

et al. 2013

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Neural development requires N-glycosylation regulation of intercellular signaling, but the requirements in synaptogenesis have not been well tested. All complex and hybrid N-glycosylation requires MGAT1 (UDP-GlcNAc:α-3-D-mannoside-β1,2-N-acetylglucosaminyltransferase I) function, and Mgat1 nulls are the most compromised N-glycosylation condition that survive long enough to permit synaptogenesis studies. At the Drosophila neuromuscular junction (NMJ), Mgat1 mutants display selective loss of lectin-defined carbohydrates in the extracellular synaptomatrix, and an accompanying accumulation of the secreted endogenous Mind the gap (MTG) lectin, a key synaptogenesis regulator. Null Mgat1 mutants exhibit strongly overelaborated synaptic structural development, consistent with inhibitory roles for complex/hybrid Nglycans in morphological synaptogenesis, and strengthened functional synapse differentiation, consistent with synaptogenic MTG functions. Synapse molecular composition is surprisingly selectively altered, with decreases in presynaptic active zone Bruchpilot (BRP) and postsynaptic Glutamate receptor subtype B (GLURIIB), but no detectable change in a wide range of other synaptic components. Synaptogenesis is driven by bidirectional trans-synaptic signals that traverse the glycan-rich synaptomatrix, and Mgat1 mutation disrupts both anterograde and retrograde signals, consistent with MTG regulation of trans-synaptic signaling. Downstream of intercellular signaling, pre-and postsynaptic scaffolds are recruited to drive synaptogenesis, and Mgat1 mutants exhibit loss of both classic Discs large 1 (DLG1) and newly defined Lethal (2) giant larvae [L(2)GL] scaffolds. We conclude that MGAT1-dependent N-glycosylation shapes the synaptomatrix carbohydrate environment and endogenous lectin localization within this domain, to modulate retention of trans-synaptic signaling ligands driving synaptic scaffold recruitment during synaptogenesis.

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“…Very little is known about the structure and functional properties of Drosophila iGluRs, and only recently was a functional reconstitution achieved for recombinant Drosophila NMJ iGluRs (Han et al, 2015). As a result, iGluRs are understudied in model organisms like Drosophila for which powerful genetic techniques have otherwise yielded numerous insights into the molecular neurobiology of synapse development and function (Charng et al, 2014; Thomas and Sigrist, 2012; Yamamoto et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Novel Functional Properties of Drosophila CNS Glutamate Receptors

Dharkar

Han

et al. 2016

Neuron

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Summary Phylogenetic analysis reveals AMPA, kainate and NMDA receptor families in insect genomes, suggesting conserved functional properties corresponding to their vertebrate counterparts. However, heterologous expression of the Drosophila kainate receptor DKaiR1D and the AMPA receptor DGluR1A revealed novel ligand selectivity at odds with the classification used for vertebrate glutamate receptor ion channels (iGluRs). DKaiR1D forms a rapidly activating and desensitizing receptor that is inhibited by both NMDA and the NMDA receptor antagonist AP5; crystallization of the KaiR1D ligand-binding domain reveals that these ligands stabilize open cleft conformations explaining their action as antagonists. Surprisingly, the AMPA receptor DGluR1A shows weak activation by its namesake agonist AMPA and also by quisqualate. Crystallization of the DGluR1A ligand-binding domain reveals amino acid exchanges that interfere with binding of these ligands. The unexpected ligand binding profiles of insect iGluRs allows classical tools to be used in novel approaches for the study of synaptic regulation.

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Glutamate Receptors in Synaptic Assembly and Plasticity: Case Studies on Fly NMJs

Cited by 22 publications

References 169 publications

Prodomain Removal Enables Neto to Stabilize Glutamate Receptors at the Drosophila Neuromuscular Junction

Prodomain Removal Enables Neto to Stabilize Glutamate Receptors at the Drosophila Neuromuscular Junction

N-glycosylation requirements in neuromuscular synaptogenesis

Novel Functional Properties of Drosophila CNS Glutamate Receptors

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