Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits
Authors: Brett S Abrahams
Ka Wan Li
Angela Giangrande
Colin McLean
Patrick Callaerts
Claudia Bagni
J Douglas Armstrong
Tilmann Achsel
Ulrike Pech
Marco Spinazzi
Alexandros K Kanellopoulos
August B Smit
Vittoria Mariano
Andre Fiala
Young Jae Woo
Journal: Cell (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Aralar; CYFIP1; Drosophila; GABA; SLC25A12 (AGC1)
Affiliations: Department of Fundamental Neurosciences, University of Lausanne, Lausanne 1005, Switzerland., Department of Fundamental Neurosciences, University of Lausanne, Lausanne 1005, Switzerland; Department of Human Genetics, KU Leuven, Leuven 3000, Belgium., Department of Human Genetics, KU Leuven, VIB Center for Brain and Disease Research Leuven, Leuven 3000, Belgium., Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., School of Informatics, University of Edinburgh, Edinburgh EH89YL, UK., Department of Molecular Neurobiology of Behaviour, University of Göttingen, Göttingen 37073, Germany., Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, 1081 HV Amsterdam, the Netherlands., Simons Initiative for the Developing Brain (SIDB), School of Informatics, University of Edinburgh, Edinburgh EH89YL, UK; Computational Biomedicine Institute (IAS-5/INM-9), Forschungszentrum Jülich, Jülich 52428, Germany., Centre National de la Recherche Scientifique, UMR7104, Institut National de la Santé et de la Recherche Medicale, Université de Strasbourg, Illkirch 67400, France., Department of Human Genetics, KU Leuven, Leuven 3000, Belgium., Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA., Department of Fundamental Neurosciences, University of Lausanne, Lausanne 1005, Switzerland; University of Rome Tor Vergata, Department of Biomedicine and Prevention, Rome 00133, Italy. Electronic address: .

Abstract:  Social impairment is frequently associated with mitochondrial dysfunction and altered neurotransmission. Although mitochondrial function is crucial for brain homeostasis, it remains unknown whether mitochondrial disruption contributes to social behavioral deficits. Here, we show that Drosophila mutants in the homolog of the human CYFIP1, a gene linked to autism and schizophrenia, exhibit mitochondrial hyperactivity and altered group behavior. We identify the regulation of GABA availability by mitochondrial activity as a biologically relevant mechanism and demonstrate its contribution to social behavior. Specifically, increased mitochondrial activity causes gamma aminobutyric acid (GABA) sequestration in the mitochondria, reducing GABAergic signaling and resulting in social deficits. Pharmacological and genetic manipulation of mitochondrial activity or GABA signaling corrects the observed abnormalities. We identify Aralar as the mitochondrial transporter that sequesters GABA upon increased mitochondrial activity. This study increases our understanding of how mitochondria modulate neuronal homeostasis and social behavior under physiopathological conditions. 

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 Note: This article has been corrected. Please see the link below: https: www.oncotarget.com article 27100 ,