title: Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission.
abstract: Neuronal communication imposes a heavy metabolic burden in maintaining ionic gradients essential for action potential firing and synaptic signalling. Although cellular metabolism is known to regulate excitatory neurotransmission, it is still unclear whether the brain's energy supply affects inhibitory signalling. Here we show that mitochondrial-derived reactive oxygen species (mROS) regulate the strength of postsynaptic GABA(A) receptors at inhibitory synapses of cerebellar stellate cells. Inhibition is strengthened through a mechanism that selectively recruits α3-containing GABA(A) receptors into synapses with no discernible effect on resident α1-containing receptors. Since mROS promotes the emergence of postsynaptic events with unique kinetic properties, we conclude that newly recruited α3-containing GABA(A) receptors are activated by neurotransmitter released onto discrete postsynaptic sites. Although traditionally associated with oxidative stress in neurodegenerative disease, our data identify mROS as a putative homeostatic signalling molecule coupling cellular metabolism to the strength of inhibitory transmission.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3B 0B1.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Accardi
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3B 0B1.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Daniels
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3B 0B1.
authors.forename: Patricia M G E
authors.initials: PM
authors.lastname: Brown
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, CH-8057, Zurich, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, CH-8057, Zurich, Switzerland.
authors.forename: Shiva K
authors.initials: SK
authors.lastname: Tyagarajan
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3B 0B1.
authors.forename: Derek
authors.initials: D
authors.lastname: Bowie
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D005680:gamma-Aminobutyric Acid; D000968:Antimycin A