Electroconvulsive Thresholds for Mouse Mutants and Strains

Description:  We are interested in detecting and characterizing new mouse models where seizure susceptibility is the primary defect. We are also interested in determining which mouse strain backgrounds are ideal for the detection and expression of seizure phenotypes.

Our approach is based on electroconvulsive threshold (ECT) tests using transcorneal electrodes - a standard for screening antiepileptic drugs (AED) in mice. We are examining three distinct ECT endpoints: minimal (clonic) seizures, maximal (tonic hindlimb) seizures and so-called "psychomotor" (partial) seizures. These endpoints involve stimulation of different brain regions and are accompanied by unique pharmacological profiles. They are potentially relevant to human seizure disorders and their AED therapies, and they may also provide general measures of the intactness and efficiency of neuronal circuits. The tests are very rapid (a few seconds per mouse), and are reported to be more robust to environmental effects than other seizure threshold tests. An important feature of our program is to determine what it takes to standardize ECT procedures across separate laboratory facilities and personnel.

The first phase of our program is to determine ECTs in a panel of common inbred strains (e.g. critical current levels to elicit a 3%, 50%, 97% response in each strain). Next, we determine whether strains respond differently to AEDs at a set threshold (e.g. what is the effective median dose at a strain's 97% response level). Once having established strain baselines for both naive electrostimulation and in the presence of AED, and compared results between laboratories, the stage is set to characterize mouse mutants of interest to determine whether they have abnormally low or high ECTs. To detect new mutants, we will also be collaborating with The Jackson Laboratory's Neuroscience Mutagenesis Facility. Once mutants are detected, they will be characterized further for susceptibility to other stimuli, (e.g. PTZ threshold), AED response and for spontaneous seizure activity (i.e. EEG).

We have almost completed the characterization of ECT baselines in over a dozen different inbred strains and several known epilepsy models, and have begun to test AEDs in several strains. Our web site provides methods, equipment descriptions and summary results. The PI (wnf@jax.org) and co-PI (Steve.White@hsc.utah.edu) will be prepared to discuss our approach and results, help transfer the technology to your lab, and potentially to arrange a collaboration when appropriate.