K Nishikawa1, Y Kidokoro. 1. Institute for Behavioral Sciences and the Department of Anesthesiology, Gunma University School of Medicine, Maebashi, Japan. nishikaw@leland.stanford.edu
Abstract
BACKGROUND: General anesthetics produce important changes in neural function, but the relation between the many individual changes produced by anesthetics in neural components and the responsiveness of the whole organism is uncertain. An analysis of genetically altered animals that have modified responses to volatile anesthetics may help to allay this uncertainty. METHODS: The authors evaluated the effect of halothane on synaptic transmission at the larval neuromuscular junction in wild-type (Ore-R) and halothane-resistant (har) mutants of Drosophila melanogaster. The body wall muscles, which are innervated by glutamatergic nerves, were voltage clamped at -60 mV using the patch-clamp technique in the whole cell configuration. Nerve-evoked excitatory junctional currents and miniature excitatory junctional currents were recorded. The effects of halothane on the amplitude of these currents were compared in Ore-R and two bar mutants derived from the Ore-R strain. The time course and frequency of miniature excitatory junctional currents also were analyzed in the presence of halothane. RESULTS: In Ore-R, halothane (1.8%; 1.01 mM) significantly reduced the amplitude of nerve-evoked excitatory junctional currents (61.9+/-17% of control, mean +/- SD; n = 7), but not that of miniature excitatory junctional currents. Conversely, in two har mutants, halothane had no effect on the amplitude of either nerve-evoked excitatory junctional currents or miniature excitatory junctional currents. In Ore-R, the frequency of miniature excitatory junctional currents was decreased significantly in the presence of halothane (0.9-2.7%; 0.52-1.46 mM), whereas halothane did not change the frequency in two har mutants. The miniature excitatory junctional current decay time constant, thought to reflect the kinetic properties of junctional glutamate receptor channels, was not changed by halothane in either the Ore-R strain or the har mutants. CONCLUSIONS: Halothane depresses synaptic transmission at the wild-type Drosophila neuromuscular junction, most likely by affecting presynaptic properties. The absence of an effect by halothane in the har mutants provides evidence that the depression of presynaptic function at the glutamate-mediated synapses is an important contributor to the way halothane alters the responsiveness of the whole animal.
BACKGROUND: General anesthetics produce important changes in neural function, but the relation between the many individual changes produced by anesthetics in neural components and the responsiveness of the whole organism is uncertain. An analysis of genetically altered animals that have modified responses to volatile anesthetics may help to allay this uncertainty. METHODS: The authors evaluated the effect of halothane on synaptic transmission at the larval neuromuscular junction in wild-type (Ore-R) and halothane-resistant (har) mutants of Drosophila melanogaster. The body wall muscles, which are innervated by glutamatergic nerves, were voltage clamped at -60 mV using the patch-clamp technique in the whole cell configuration. Nerve-evoked excitatory junctional currents and miniature excitatory junctional currents were recorded. The effects of halothane on the amplitude of these currents were compared in Ore-R and two bar mutants derived from the Ore-R strain. The time course and frequency of miniature excitatory junctional currents also were analyzed in the presence of halothane. RESULTS: In Ore-R, halothane (1.8%; 1.01 mM) significantly reduced the amplitude of nerve-evoked excitatory junctional currents (61.9+/-17% of control, mean +/- SD; n = 7), but not that of miniature excitatory junctional currents. Conversely, in two har mutants, halothane had no effect on the amplitude of either nerve-evoked excitatory junctional currents or miniature excitatory junctional currents. In Ore-R, the frequency of miniature excitatory junctional currents was decreased significantly in the presence of halothane (0.9-2.7%; 0.52-1.46 mM), whereas halothane did not change the frequency in two har mutants. The miniature excitatory junctional current decay time constant, thought to reflect the kinetic properties of junctional glutamate receptor channels, was not changed by halothane in either the Ore-R strain or the har mutants. CONCLUSIONS:Halothane depresses synaptic transmission at the wild-type Drosophila neuromuscular junction, most likely by affecting presynaptic properties. The absence of an effect by halothane in the har mutants provides evidence that the depression of presynaptic function at the glutamate-mediated synapses is an important contributor to the way halothane alters the responsiveness of the whole animal.
Authors: Jessica X Chong; Margaret J McMillin; Kathryn M Shively; Anita E Beck; Colby T Marvin; Jose R Armenteros; Kati J Buckingham; Naomi T Nkinsi; Evan A Boyle; Margaret N Berry; Maureen Bocian; Nicola Foulds; Maria Luisa Giovannucci Uzielli; Chad Haldeman-Englert; Raoul C M Hennekam; Paige Kaplan; Antonie D Kline; Catherine L Mercer; Malgorzata J M Nowaczyk; Jolien S Klein Wassink-Ruiter; Elizabeth W McPherson; Regina A Moreno; Angela E Scheuerle; Vandana Shashi; Cathy A Stevens; John C Carey; Arnaud Monteil; Philippe Lory; Holly K Tabor; Joshua D Smith; Jay Shendure; Deborah A Nickerson; Michael J Bamshad Journal: Am J Hum Genet Date: 2015-02-12 Impact factor: 11.025