General anaesthetics produce loss of consciousness by acting on multiple mechanisms in parallel. These mechanisms can be broadly separated into pre- and postsynaptic effects, involving protein targets on either side of chemical synapses in the brain. Post-synaptic targets include inhibitory ion channels such as GABA(A) receptors. Specific GABA(A) receptor mutations have been engineered in mice that block this postsynaptic effect. On the other hand, pre-synaptic mechanisms of general anaesthesia are less understood. There is however also way to potentially block the presynaptic effects of anaesthetics: expressing a truncated version of a protein called syntaxin1A has been found to produce anaesthesia resistance across a range of systems, including nematodes, flies, and rodent neuronal cultures. However, this presynaptic manipulation has never been tested in a live mouse model. In this project, we will engineer a mouse expressing the mutant protein and test whether this produces a level of resistance to general anaesthetics. Further, we anticipate that a GABA(A)-syntaxin1A double-mutant mouse should be highly resistant across a range of anaesthesia endpoints. This project will disambiguate the relative contribution of these distinct target mechanisms of general anaesthesia, and in this way inform the design of effective reversal agents to help expedite recovery.
Professor André Van Zundert, Associate Professor Michelle Roets, Royal Brisbane and Women’s Hospital, The University of Queensland, Brisbane, QLD.
The project was awarded A$70,000 funding through the ANZCA research grants program for 2026.