Transcriptional Regulation of the Glutamate/GABA/Glutamine Cycle in Adult Glia Controls Motor Activity and Seizures in Drosophila
- David Mazaud1,
- Benjamin Kottler1,
- Catarina Gonçalves-Pimentel1,
- Sandra Proelss1,
- Nadine Tüchler1,
- Celine Deneubourg1,
- Yoshihiro Yuasa2,3,4,5,
- Celine Diebold2,3,4,5,
- Heinz Jungbluth1,
- Eric C. Lai6,
- Frank Hirth1,
- Angela Giangrande2,3,4,5, and
- Manolis Fanto1
- 1Department of Basic and Clinical Neuroscience, King's College London, SE5 9NU London, United Kingdom,
- 2Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France,
- 3Centre National de la Recherche Scientifique, UMR7104, Illkirch, France,
- 4Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France,
- 5Université de Strasbourg, 67404 Illkirch, France, and
- 6Department of Developmental Biology, Sloan-Kettering Institute, New York, New York 10065
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Author contributions: D.M. and M.F. designed research; D.M., B.K., C.G.-P., S.P., N.T., and C. Deneubourg performed research; D.M., B.K., and M.F. analyzed data; D.M. wrote the first draft of the paper; D.M., B.K., C.G.-P., H.J., F.H., and A.G. edited the paper; Y.Y., C. Diebold, E.C.L., F.H., and A.G. contributed unpublished reagents/analytic tools; M.F. wrote the paper.
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.
- Received July 18, 2018.
- Revision received April 9, 2019.
- Accepted April 11, 2019.
- Copyright © 2019 Mazaud et al.
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