Synapse-specific trapping of Syntaxin1a into nanoclusters by the general anesthetic isoflurane

Summary General anesthetics disrupt brain network dynamics through multiple pathways, predominately through post-synaptic potentiation of GABA A R and pre-synaptic inhibition of neuroexocytosis. Common clinical general anesthetic drugs, such as propofol and isoflurane, have been shown to interact and interfere with a core component of the exocytic release machinery, Syntaxin1A, to cause impaired neurotransmitter release. Recent in vitro studies however suggest that these drugs to not affect all synapse subtypes equally. We investigated the role of Syntaxin1A in multiple neurotransmitter systems under isoflurane general anesthesia in the adult Drosophila brain using live-cell super resolution microscopy and optogenetic readouts of exocytosis. We found that effects of isoflurane anesthesia were neuron specific and only impaired Syntaxin1A activity in excitatory neurons at cholinergic synapses, but not inhibitory GABAergic or glutamatergic neurons. These results indicate that general anesthetics could work by producing successive bouts of inhibition across the brain, by reducing neuroexocytosis from excitatory neurons specifically as well as silencing arousal systems through GABA A R potentiation.