Wrapping glia regulates neuronal signaling speed and precision in the peripheral nervous system of Drosophila

Kottmeier, Rita; Bittern, Jonas; Schoofs, Andreas; Scheiwe, Frederieke; Matzat, Till; Pankratz, Michael J.; Klämbt, Christian

doi:10.1038/s41467-020-18291-1

Cited by 53 publications

(58 citation statements)

References 104 publications

(161 reference statements)

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“…A large inhibitory RNA (RNAi)-based screen for behavioral phenotypes resulting from gene inactivation in glial cells has identified a number of bang-sensitive mutants, which are orthologs of human epilepsy-associated genes with roles in glial and, interestingly, glia–neuron interactions 16 , 74 , 75 .…”

Section: Model-based Steps Towards Effective Epilepsy Treatmentmentioning

confidence: 99%

Investigating rare and ultrarare epilepsy syndromes with Drosophila models

Lasko¹,

Lüthy²

2021

Fac Rev

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One in three epilepsy cases is drug resistant, and seizures often begin in infancy, when they are life-threatening and when therapeutic options are highly limited. An important tool for prioritizing and validating genes associated with epileptic conditions, which is suitable for large-scale screening, is disease modeling in Drosophila . Approximately two-thirds of disease genes are conserved in Drosophila , and gene-specific fly models exhibit behavioral changes that are related to symptoms of epilepsy. Models are based on behavior readouts, seizure-like attacks and paralysis following stimulation, and neuronal, cell-biological readouts that are in the majority based on changes in nerve cell activity or morphology. In this review, we focus on behavioral phenotypes. Importantly, Drosophila modeling is independent of, and complementary to, other approaches that are computational and based on systems analysis. The large number of known epilepsy-associated gene variants indicates a need for efficient research strategies. We will discuss the status quo of epilepsy disease modelling in Drosophila and describe promising steps towards the development of new drugs to reduce seizure rates and alleviate other epileptic symptoms.

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Section: Model-based Steps Towards Effective Epilepsy Treatmentmentioning

confidence: 99%

Investigating rare and ultrarare epilepsy syndromes with Drosophila models

Lasko¹,

Lüthy²

2021

Fac Rev

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“…We hypothesized that impaired transport of synaptic BRP could be due to a shortage in metabolic energy supply within the neuron which is known to depend on glial cells (Edgar et al, 2004; Edgar et al, 2009; Griffiths et al, 1998; Nave, 2010) and at the Drosophila PNS on WG (Kottmeier et al, 2020). Here especially the Astrocyte‐Neuron Lactate Shuttle Hypothesis (Pellerin & Magistretti, 1994) states that glial cells energetically support neurons by shuttling alanine and lactate via monocarboxylate transporters (MCTs) to fuel neuronal mitochondria in Drosophila and mice (Funfschilling et al, 2012; Y. Lee et al, 2012; Liu, MacKenzie, Putluri, Maletic‐Savatic, & Bellen, 2017; Machler et al, 2016; Pierre & Pellerin, 2005).…”

Section: Resultsmentioning

confidence: 99%

“…SPG control ion homeostasis and form septate junctions (SJs), which block paracellular diffusion and thus seal the nervous system from the hemolymph (Leiserson, Harkins, & Keshishian, 2000; Schwabe, Bainton, Fetter, Heberlein, & Gaul, 2005; Stork et al, 2008; Unhavaithaya & Orr‐Weaver, 2012). WG resemble the non‐myelinating vertebrate Schwann cells that engulf axon bundles to form Remak fibers, and are thought to function in metabolic/ion homeostasis and support AP propagation (Kottmeier et al, 2020; Leiserson et al, 2000; Li, Russo, & DiAntonio, 2019).…”

Section: Introductionmentioning

confidence: 99%

Glial Synaptobrevin mediates peripheral nerve insulation, neural metabolic supply, and is required for motor function

Böhme

McCarthy

Blaum

et al. 2021

Glia

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Peripheral nerves contain sensory and motor neuron axons coated by glial cells whose interplay ensures function, but molecular details are lacking. SNARE‐proteins mediate the exchange and secretion of cargo by fusing vesicles with target organelles, but how glial SNAREs contribute to peripheral nerve function is largely unknown. We, here, identify non‐neuronal Synaptobrevin (Syb) as the essential vesicular SNARE in Drosophila peripheral glia to insulate and metabolically supply neurons. We show that tetanus neurotoxin light chain (TeNT‐LC), which potently inhibits SNARE‐mediated exocytosis from neurons, also impairs peripheral nerve function when selectively expressed in glia, causing nerve disintegration, defective axonal transport, tetanic muscle hyperactivity, impaired locomotion, and lethality. While TeNT‐LC disrupts neural function by cleaving neuronal Synaptobrevin (nSyb), it targets non‐neuronal Synaptobrevin (Syb) in glia, which it cleaves at low rates: Glial knockdown of Syb (but not nSyb) phenocopied glial TeNT‐LC expression whose effects were reverted by a TeNT‐LC‐insensitive Syb mutant. We link Syb‐necessity to two distinct glial subtypes: Impairing Syb function in subperineurial glia disrupted nerve morphology, axonal transport, and locomotion, likely, because nerve‐isolating septate junctions (SJs) could not form as essential SJ components (like the cell adhesion protein Neurexin‐IV) were mistargeted. Interference with Syb in axon‐encircling wrapping glia left nerve morphology and locomotion intact but impaired axonal transport, likely because neural metabolic supply was disrupted due to the mistargeting of metabolite shuffling monocarboxylate transporters. Our study identifies crucial roles of Syb in various glial subtypes to ensure glial‐glial and glial‐neural interplay needed for proper nerve function, animal motility, and survival.

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“…The former glia type is known to be a major constituent of insect BBB/BNB [ 15 , 16 ]. The latter type of glia serves as non-myelinating cells that ensheath axons in peripheral nerves to provide both proper conductance and nerve integrity [ 15 , 28 ]. We suppose that the observed glia impairment may be associated with the sws function.…”

Section: Discussionmentioning

confidence: 99%

“…After embryogenesis, WG cells begin to differentiate [ 27 ]. Disturbances in the development of WG affect the normal functioning of the nervous system [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Morpho-Functional Consequences of Swiss Cheese Knockdown in Glia of Drosophila melanogaster

Ryabova

Melentev

Komissarov

et al. 2021

Cells

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Glia are crucial for the normal development and functioning of the nervous system in many animals. Insects are widely used for studies of glia genetics and physiology. Drosophila melanogaster surface glia (perineurial and subperineurial) form a blood–brain barrier in the central nervous system and blood–nerve barrier in the peripheral nervous system. Under the subperineurial glia layer, in the cortical region of the central nervous system, cortex glia encapsulate neuronal cell bodies, whilst in the peripheral nervous system, wrapping glia ensheath axons of peripheral nerves. Here, we show that the expression of the evolutionarily conserved swiss cheese gene is important in several types of glia. swiss cheese knockdown in subperineurial glia leads to morphological abnormalities of these cells. We found that the number of subperineurial glia nuclei is reduced under swiss cheese knockdown, possibly due to apoptosis. In addition, the downregulation of swiss cheese in wrapping glia causes a loss of its integrity. We reveal transcriptome changes under swiss cheese knockdown in subperineurial glia and in cortex + wrapping glia and show that the downregulation of swiss cheese in these types of glia provokes reactive oxygen species acceleration. These results are accompanied by a decline in animal mobility measured by the negative geotaxis performance assay.

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Wrapping glia regulates neuronal signaling speed and precision in the peripheral nervous system of Drosophila

Cited by 53 publications

References 104 publications

Investigating rare and ultrarare epilepsy syndromes with Drosophila models

Investigating rare and ultrarare epilepsy syndromes with Drosophila models

Glial Synaptobrevin mediates peripheral nerve insulation, neural metabolic supply, and is required for motor function

Morpho-Functional Consequences of Swiss Cheese Knockdown in Glia of Drosophila melanogaster

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