Syntaxin1A-mediated Resistance and Hypersensitivity to Isoflurane in Drosophila melanogaster.
BACKGROUND
Recent evidence suggests that general anesthetics activate endogenous sleep pathways, yet this mechanism cannot explain the entirety of general anesthesia. General anesthetics could disrupt synaptic release processes, as previous work in Caenorhabditis elegans and in vitro cell preparations suggested a role for the soluble NSF attachment protein receptor protein, syntaxin1A, in mediating resistance to several general anesthetics. The authors questioned whether the syntaxin1A-mediated effects found in these reductionist systems reflected a common anesthetic mechanism distinct from sleep-related processes.


METHODS
Using the fruit fly model, Drosophila melanogaster, the authors investigated the relevance of syntaxin1A manipulations to general anesthesia. The authors used different behavioral and electrophysiological endpoints to test the effect of syntaxin1A mutations on sensitivity to isoflurane.


RESULTS
The authors found two syntaxin1A mutations that confer opposite general anesthesia phenotypes: syxH3-C, a 14-amino acid deletion mutant, is resistant to isoflurane (n = 40 flies), and syxKARRAA, a strain with two amino acid substitutions, is hypersensitive to the drug (n = 40 flies). Crucially, these opposing effects are maintained across different behavioral endpoints and life stages. The authors determined the isoflurane sensitivity of syxH3-C at the larval neuromuscular junction to assess effects on synaptic release. The authors find that although isoflurane slightly attenuates synaptic release in wild-type animals (n = 8), syxH3-C preserves synaptic release in the presence of isoflurane (n = 8).


CONCLUSIONS
The study results are evidence that volatile general anesthetics target synaptic release mechanisms; in addition to first activating sleep pathways, a major consequence of these drugs may be to decrease the efficacy of neurotransmission.
From the University of Queensland, Queensland Brain Institute, Brisbane, Australia (O.H.Z., B.K., R.F., R.D., A.T.B., B.v.S.); School of Medical Science and Griffith Health Institute, Griffith University Gold Coast Campus, Gold Coast, Queensland, Australia (H.M., S.K.); and the University of Queensland, School of Biomedical Sciences, Brisbane, Australia (N.L., S.K.).
Oressia H
OH
Zalucki
Hareesh
H
Menon
Benjamin
B
Kottler
Richard
R
Faville
Rebecca
R
Day
Adekunle T
AT
Bademosi
Nickolas
N
Lavidis
Shanker
S
Karunanithi
Bruno
B
van Swinderen
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster; D004351:Drug Resistance / Q000235:genetics*; D006967:Hypersensitivity / Q000235:genetics*; D007530:Isoflurane / Q000494:pharmacology*; D007814:Larva; D008124:Locomotion / Q000187:drug effects; D009154:Mutation; D009469:Neuromuscular Junction / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000502:physiology*; D013216:Reflex, Startle; D012890:Sleep / Q000187:drug effects
D018685:Anesthetics, Inhalation; D029721:Drosophila Proteins; D018377:Neurotransmitter Agents; D050765:Qa-SNARE Proteins; C578392:syntaxin, Drosophila; D007530:Isoflurane