Mechanisms of sleep and general anaesthesia in Drosophila melanogaster: the unresponsive brain

Abstract

General anaesthetics are amongst the most important drugs in modern medicine. However, the mechanism by which they act to produce a loss of consciousness and stop responses to the external world remain unknown. It has been proposed that anaesthetics may act postsynaptically, by binding inhibitory channels to increase inhibition across the brain. More specifically, they might potentiate the endogenous inhibitory circuits already used for other behaviours. There are similarities between the state of general anaesthesia and sleep, and strong evidence that some of the circuits general anaesthetics may act upon are those that control sleep. An alternative presynaptic mechanism of anaesthesia has also been proposed, and a growing body of evidence has shown changes in synaptic release efficacy in response to these drugs.

The effects of the general anaesthetic propofol on Drosophila larvae

“…Previous work in our lab has demonstrated that adult flies expressing syntaxin H3-N are resistant to the general anaesthetic isoflurane (Troup, 2018). I hypothesised that larvae would be similarly resistant.…”

“…Drosophila has already been used to probe for anaesthetic targets (Leibovitch et al, 1995;Zalucki et al, 2015b;Troup, 2018) and its flexibility as a model has allowed for anaesthetics to be studied at many different levels from the synapse (Bademosi et al, 2018) to the brain (Cohen et al, 2016).…”

“…A similar truncated isoform, syntaxin 227 , rescues the effect of propofol on syntaxin1A mobility in mammalian cell culture (Bademosi et al, 2018) (figure 3.1B). In adult flies, syntaxin 227 expression can confer resistance to propofol and isoflurane (Troup, 2018). Furthermore, syntaxin 227 has been shown to protect synaptic release in the 1b boutons of the larval NMJ (Karunanithi et al, manuscript in preparation).…”

“…However, in contrast with syntaxin 227 , syntaxin H3-N does not interact with SNAP25 (Wu et la., 1999;Bademosi et al, 2018). Syntaxin H3-N expression also confers resistance to isoflurane and propofol in adult flies (Troup, 2018). It therefore seems likely that this resistance could be observed in larval behaviour.…”

“…Additionally, expression of syntaxin 227 confers resistance to both propofol and isoflurane in adult flies (Troup, 2018). A deletion mutant, syntaxin H3-N , which is missing the N-terminus of the H3 domain (Wu et al, 1999), has also been shown to rescue propofol-induced changes in syntaxin1A mobility (Bademosi et al, 2018) and has been demonstrated to confer resistance to isoflurane and propofol in adult flies (Troup, 2018) (figure 3.1B).…”