A Genome-Wide RNAi Screen in Caenorhabditis elegans Identifies the Nicotinic Acetylcholine Receptor Subunit ACR-7 as an Antipsychotic Drug Target

We report a genome-wide rna interference (rnai) screen for suppressors of clozapine-induced larval arrest (scla genes) in caenorhabditis elegans,the first genetic suppressor screen for antipsychotic drug (apd) targets in an animal. the screen identifies 40 suppressors,including the α-like nicotinic acetylcholine receptor (nachr) homolog acr-7. we validate the requirement for acr-7 by showing that acr-7 knockout suppresses clozapine-induced larval arrest and that expression of a full-length translational gfp fusion construct rescues this phenotype. nachr agonists phenocopy the developmental effects of clozapine,while nachr antagonists partially block these effects. acr-7 is strongly expressed in the pharynx,and clozapine inhibits pharyngeal pumping. acr-7 knockout and nachr antagonists suppress clozapine-induced inhibition of pharyngeal pumping. these findings suggest that clozapine activates acr-7 channels in pharyngeal muscle,leading to tetanus of pharyngeal muscle with consequent larval arrest. no apds are known to activate nachrs,but a number of studies indicate that α7-nachr agonists may prove effective for the treatment of psychosis. α-like nachr signaling is a mechanism through which clozapine may produce its therapeutic and/or toxic effects in humans,a hypothesis that could be tested following identification of the mammalian ortholog of c. elegans acr-7. © 2013 saur et al.