Glutamatergic neurotransmission links sensitivity to volatile anesthetics with mitochondrial function
Zimin, Pavel I. (Seattle Children's Research Institute. Center for Developmental Therapeutics (Seattle, Estats Units d'Amèrica))
Woods, Christian B. (Seattle Children's Research Institute. Center for Developmental Therapeutics (Seattle, Estats Units d'Amèrica))
Quintana Romero, Albert (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Ramirez, Jan-Marino (Seattle Children's Research Institute. Center for Integrative Brain Research (Seattle, Estats Units d'Amèrica))
Morgan, Philip G. (Seattle Children's Research Institute. Center for Developmental Therapeutics (Seattle, Estats Units d'Amèrica))
Sendensky, Margaret M. (Seattle Children's Research Institute. Center for Developmental Therapeutics (Seattle, Estats Units d'Amèrica))

Data:	2016
Resum:	An enigma of modern medicine has persisted for over 150 years. The mechanisms by which volatile anesthetics (VAs) produce their effects (loss of consciousness, analgesia, amnesia, and immobility) remain an unsolved mystery. Many attractive putative molecular targets have failed to produce a significant effect when genetically tested in whole-animal models [1-3]. However, mitochondrial defects increase VA sensitivity in diverse organisms from nematodes to humans [4-6]. Ndufs4 knockout (KO) mice lack a subunit of mitochondrial complex I and are strikingly hypersensitive to VAs yet resistant to the intravenous anesthetic ketamine [7]. The change in VA sensitivity is the largest reported for a mammal. Limiting NDUFS4 loss to a subset of glutamatergic neurons recapitulates the VA hypersensitivity of Ndufs4(KO) mice, while loss in GABAergic or cholinergic neurons does not. Baseline electrophysiologic function of CA1 pyramidal neurons does not differ between Ndufs4(KO) and control mice. Isoflurane concentrations that anesthetize only Ndufs4(KO) mice (0. 6%) decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) only in Ndufs4(KO) CA1 neurons, while concentrations effective in control mice (1. 2%) decreased sEPSC frequencies in both control and Ndufs4(KO) CA1 pyramidal cells. Spontaneous inhibitory postsynaptic currents (sIPSCs) were not differentially affected between genotypes. The effects of isoflurane were similar on evoked field excitatory postsynaptic potentials (fEPSPs) and paired pulse facilitation (PPF) in KO and control hippocampal slices. We propose that CA1 presynaptic excitatory neurotransmission is hypersensitive to isoflurane in Ndufs4(KO) mice due to the inhibition of pre-existing reduced complex I function, reaching a critical reduction that can no longer meet metabolic demands.
Nota:	Actualment, Albert Quintana Romero desenvolupa la seva recerca a l'Institut de Neurociències de la Universitat Autònoma de Barcelona
Nota:	Altres ajuts: NIH/GM105696
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Publicat a:	Current biology, Vol. 26, Issue 16 (August 2016) , p. 2194-2201, ISSN 0960-9822

DOI: 10.1016/j.cub.2016.06.020
PMID: 27498564

Post-print 26 p, 2.1 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Neurociències (INc)
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