title: Glutamatergic Neurotransmission Links Sensitivity to Volatile Anesthetics with Mitochondrial Function.
abstract: 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.
authors: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA. Electronic address: pavel.zimin@seattlechildrens.org.
authors: Pavel I
authors: PI
authors: Zimin
authors: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors: Christian B
authors: CB
authors: Woods
authors: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors: Albert
authors: A
authors: Quintana
authors: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors: Jan-Marino
authors: JM
authors: Ramirez
authors: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors: Philip G
authors: PG
authors: Morgan
authors: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors: Margaret M
authors: MM
authors: Sedensky
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000378:metabolism; D005260:Female; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission
chemical_list: D018685:Anesthetics, Inhalation; D007530:Isoflurane; D042967:Electron Transport Complex I