Skip to Content
Merck
  • Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits.

Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits.

Cell (2020-03-24)
Alexandros K Kanellopoulos, Vittoria Mariano, Marco Spinazzi, Young Jae Woo, Colin McLean, Ulrike Pech, Ka Wan Li, J Douglas Armstrong, Angela Giangrande, Patrick Callaerts, August B Smit, Brett S Abrahams, Andre Fiala, Tilmann Achsel, Claudia Bagni
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Erioglaucine disodium salt, coloring dye
Sigma-Aldrich
Pyridoxal 5′-phosphate hydrate, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
(+)-Sodium L-ascorbate, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
γ-Aminobutyric acid, ≥99%
Sigma-Aldrich
Sodium succinate dibasic hexahydrate, ReagentPlus®, ≥99%
Sigma-Aldrich
N,N,N′,N′-Tetramethyl-p-phenylenediamine dihydrochloride, ≥95%, powder
Sigma-Aldrich
Sodium pyruvate, ReagentPlus®, ≥99%
Sodium valproate, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Potassium cyanide, BioUltra, ≥98.0% (AT)
Sigma-Aldrich
D.E.R. 332, used as embedding medium
Sigma-Aldrich
Tetramethylrhodamine ethyl ester perchlorate, suitable for fluorescence, ≥90% (HPCE)
Sigma-Aldrich
Rotenone, ≥95%
Sigma-Aldrich
L-Glutamic acid monosodium salt hydrate, ≥99% (HPLC), powder
Sigma-Aldrich
Carbonyl cyanide 3-chlorophenylhydrazone, ≥97% (TLC), powder
Sigma-Aldrich
Rhodamine 123, mitochondrial specific fluorescent dye
Sigma-Aldrich
Oligomycin from Streptomyces diastatochromogenes, ≥90% total oligomycins basis (HPLC)
Sigma-Aldrich
Antimycin A from Streptomyces sp.
Sigma-Aldrich
L-(−)-Malic acid, ≥95% (titration)
Sigma-Aldrich
Valproic acid sodium salt, 98%