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.
| Original language | English |
|---|---|
| Pages (from-to) | 1178-1197.e20 |
| Number of pages | 41 |
| Journal | Cell |
| Volume | 180 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 19 Mar 2020 |
Funding
This work was supported by VIB , KUL Funds Opening the Future (OTF), the Queen Elisabeth Foundation (Belgium), SNSF 310030-182651 , NCCR Synapsy 51NF40-158776 (Switzerland), Novartis (Switzerland), and PRIN 201789LFKB to C.B. Additional funds were from HEALTH-2009-2.1.2-1 EU-FP7 “SynSys” (to C.B., A.B.S., and J.D.A.), the German Research Foundation ( SFB 889/B04 ), and the Bernstein Center for Computational Neuroscience Göttingen (grant 01GQ1005A ) (to U.P. and A.F.) and INSERM , CNRS , and ANR-10-LABX-0030-INRT (to A.G.). A.K.K. was the recipient of the Autism Speaks Meixner translational postdoctoral fellowship (grant 9728 ) and supported by the Greek State Scholarships Foundation IKY , the Fondation Sophie Afenduli , and Autism Research Institute (ARI). M.S. was the recipient of an EMBO long-term fellowship ( ALTF 648-2013 ) and supported by funding to Bart De Strooper. P.C. was supported by a grant from VIB and FWO ( G065408.N10 and G078914N ). We thank Efthimios Skoulakis, Ronald Davis, Rob Jackson, Brett H. Graham, Hugo Bellen, and Patrik Verstreken for fly stocks and reagents. We acknowledge the Developmental Hybridoma Studies Bank for antibodies, the Bloomington Drosophila Stock Center and Vienna Drosophila Resource Center for resources, and Flybase for essential information. We thank Annick Crevoisier and Eef Lemmens for administrative assistance. We are grateful to Vassil Altanov, Elisa Cappuyns, and Lysimachos Zografos for preliminary data and Kris Dickson and Richard Benton for critical reading of this manuscript. We thank Ilse Smolders and Ann Van Eeckhaut for help with the initial HPLC analysis. We are particularly grateful to Dr. Julijana Ivanisevic and Dr. Hector Gallart-Ayala at the Metabolomic Unit, University of Lausanne, for excellent advice, support, and analysis of the metabolites and Federico Caicci at the electron microscopy facility of the Department of Biology, University of Padova for the excellent TEM analysis of the mitochondria. The graphical model was made by Servier Medical Art ( https://www.servier.com/ ). This paper is dedicated to the memory of an inspiring mentor and visionary scientist, Fotis C. Kafatos.
| Funders | Funder number |
|---|---|
| KUL | |
| NCCR | 51NF40-158776, PRIN 201789LFKB |
| Queen Elisabeth Foundation | |
| Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung | 310030-182651 |
| Vlaams Instituut voor Biotechnologie |
Keywords
- Aralar
- autism
- CYFIP1
- Drosophila
- GABA
- mitochondrial activity
- mitochondrial membrane potential
- schizophrenia
- SLC25A12 (AGC1)
- social group behavior