Mouse strains will be developed to test the concept of selective neuronal silencing using a combined genetic and pharmacological approach. The strategy employs the glutamate-gated chloride channel / ivermectin (GluCl / IVM). The mice will selectively express optimized GluCl channels, with behavioral testing as appropriate for each strain. Three """"""""proof of concept"""""""" conventional mouse strains are envisioned that have straightforward behavioral assays. The first will employ the promoter for TrkA, a peripheral nervous system promoter. The assay is pain. The second, for retinal ganglion cells, will employ the Brn3b promoter. The assays are visual behavior and visual evoked potentials. The third, for the cerebellum, will employ the L7 promoter. The assay is ataxia. For each strain, experiments will detail the extent, IVM concentration dependence, onset, and recovery time course of silencing based on the behavioral assays. Pitfalls seem surmountable. The project seeks to develop a technique that permits one to interfere deliberately, delicately, specifically, transiently and reversibly with discrete subpopulations of genetically identified neurons in mice. If the """"""""proof of concept"""""""" experiments succeed, an R01 grant will be sought to extend and exploit the system. There are important applications in many fields of neuroscience.
| Lerchner, Walter; Xiao, Cheng; Nashmi, Raad et al. (2007) Reversible silencing of neuronal excitability in behaving mice by a genetically targeted, ivermectin-gated Cl- channel. Neuron 54:35-49 |
