Insights & Perspectives
Explaining general anesthesia: A two-step hypothesis linking sleep circuits and the synaptic release machinery
Version of Record online: 22 JAN 2014
© 2014 WILEY Periodicals, Inc.
Volume 36, Issue 4, pages 372–381, April 2014
How to Cite
van Swinderen, B. and Kottler, B. (2014), Explaining general anesthesia: A two-step hypothesis linking sleep circuits and the synaptic release machinery. Bioessays, 36: 372–381. doi: 10.1002/bies.201300154
- Issue online: 5 MAR 2014
- Version of Record online: 22 JAN 2014
- ARC fellowship. Grant Numbers: FT100100725, ARC DP1093968
- Caenorhabditis elegans;
- general anesthesia;
Several general anesthetics produce their sedative effect by activating endogenous sleep pathways. We propose that general anesthesia is a two-step process targeting sleep circuits at low doses, and synaptic release mechanisms across the entire brain at the higher doses required for surgery. Our hypothesis synthesizes data from a variety of model systems, some which require sleep (e.g. rodents and adult flies) and others that probably do not sleep (e.g. adult nematodes and cultured cell lines). Non-sleeping systems can be made insensitive (or hypersensitive) to some anesthetics by modifying a single pre-synaptic protein, syntaxin1A. This suggests that the synaptic release machinery, centered on the highly conserved SNARE complex, is an important target of general anesthetics in all animals. A careful consideration of SNARE architecture uncovers a potential mechanism for general anesthesia, which may be the primary target in animals that do not sleep, but a secondary target in animals that sleep.