Selective Electrical Silencing of Mammalian Neurons In Vitro by the Use of Invertebrate Ligand-Gated Chloride Channels

Selectively reducing the excitability of specific neurons will (1) allow for the creation of animal models of human neurological disorders and (2) provide insight into the global function of specific sets of neurons. We focus on a combined genetic and pharmacological approach to silence neurons electrically. We express invertebrate ivermectin (IVM)-sensitive chloride chan-nels (Caenorhabditis elegans GluCl and ) with a Sindbis virus and then activate these channels with IVM to produce inhibition via a Cl conductance. We constructed a three-cistron Sindbis virus that expresses the and subunits of a glutamate-gated chloride channel (GluCl) along with the green fluorescent pro-tein (EGFP) marker. Expression of the C. elegans channel does not affect the normal spike activity or GABA/glutamate postsyn-aptic currents of cultured embryonic day 18 hippocampal neu-rons. At concentrations as low as 5 nM, IVM activates a C