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Transcriptional regulation of the Glutamate/GABA/Glutamine cycle in adult glia controls motor activity and seizures in Drosophila

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)5269-5283
Number of pages15
JournalJournal of Neuroscience
Volume39
Issue number27
Early online date7 May 2019
DOIs
Accepted/In press11 Apr 2019
E-pub ahead of print7 May 2019
Published3 Jul 2019

Documents

  • Transcriptional regulation of the_MAZAUD_Accepted11April2019_GREEN VoR (CC BY)

    Transcriptional_regulation_of_the_MAZAUD_Accepted11April2019_GOLD_VoR_CC_BY_.pdf, 5 MB, application/pdf

    Uploaded date:01 Aug 2019

    Version:Final published version

    Licence:CC BY

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King's Authors

Abstract

The fruitfly Drosophila melanogaster has been extensively used as a genetic model for the maintenance of nervous system's functions. Glial cells are of utmost importance in regulating the neuronal functions in the adult organism and in the progression of neurological pathologies. Through a microRNA-based screen in adult Drosophila glia, we uncovered the essential role of a major glia developmental determinant, repo, in the adult fly. Here, we report that Repo expression is continuously required in adult glia to transcriptionally regulate the highly conserved function of neurotransmitter recycling in both males and females. Transient loss of Repo dramatically shortens fly lifespan, triggers motor deficits, and increases the sensibility to seizures, partly due to the impairment of the glutamate/GABA/glutamine cycle. Our findings highlight the pivotal role of transcriptional regulation of genes involved in the glutamate/GABA/glutamine cycle in glia to control neurotransmitter levels in neurons and their behavioral output. The mechanism identified here in Drosophila exemplifies how adult functions can be modulated at the transcriptional level and suggest an active synchronized regulation of genes involved in the same pathway. The process of neurotransmitter recycling is of essential importance in human epileptic and psychiatric disorders and our findings may thus have important consequences for the understanding of the role that transcriptional regulation of neurotransmitter recycling in astrocytes has in human disease.SIGNIFICANCE STATEMENT Glial cells are an essential support to neurons in adult life and have been involved in a number of neurological disorders. What controls the maintenance and modulation of glial functions in adult life is not fully characterized. Through a miR overexpression screen in adult glia in Drosophila, we identify an essential role in adult glia of repo, which directs glial differentiation during embryonic development. Repo levels modulate, via transcriptional regulation, the ability of glial cells to support neurons in the glutamate/GABA/glutamine cycle. This leads to significant abnormalities in motor behavior as assessed through a novel automated paradigm. Our work points to the importance of transcriptional regulation in adult glia for neurotransmitter recycling, a key process in several human neurological disorders.

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