Reversible silencing of neuronal excitability in behaving mice by a genetically targeted, ivermectin-gated Cl- channel.
Several genetic strategies for inhibiting neuronal function in mice have been described, but no system that directly suppresses membrane excitability and is triggered by a systemically administered drug, has been validated in awake behaving animals. We expressed unilaterally in mouse striatum a modified heteromeric ivermectin (IVM)-gated chloride channel from C. elegans (GluClalphabeta), systemically administered IVM, and then assessed amphetamine-induced rotational behavior. Rotation was observed as early as 4 hr after a single intraperitoneal IVM injection (10 mg/kg), reached maximal levels by 12 hr, and was almost fully reversed by 4 days. Multiple cycles of silencing and recovery could be performed in a single animal. In striatal slice preparations from GluClalphabeta-expressing animals, IVM rapidly suppressed spiking. The two-subunit GluCl/IVM system permits "intersectional" strategies designed to increase the cellular specificity of silencing in transgenic animals.
Lerchner
Walter
W
Division of Biology 216-76, California Institute of Technology, Pasadena, CA 91125, USA.
Xiao
Cheng
C
Nashmi
Raad
R
Slimko
Eric M
EM
van Trigt
Laurent
L
Lester
Henry A
HA
Anderson
David J
DJ
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels / Q000187:drug effects / Q000235:genetics; D003342:Corpus Striatum / Q000166:cytology; D004347:Drug Interactions; D015870:Gene Expression; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics; D007559:Ivermectin / Q000494:pharmacology*; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013997:Time Factors
D000977:Antiparasitic Agents; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels; D008164:Luminescent Proteins; D007559:Ivermectin; D000661:Amphetamine; D010751:Phosphopyruvate Hydratase