Epilepsy afflicts more than 1 percent of the population. Antiepileptic drugs control seizures in 75 percent of patients, but have side effects and many patients are refractory to therapy. About half of all epilepsies has a genetic component, and several human genes have been identified for rarer forms. Despite this important progress, genes for the most common idiopathic epilepsies are completely unknown and may be difficult to approach given what is known of their complex inheritance. We therefore turn to mouse models to provide candidate mechanisms and targets. Although mice continue to be important for evaluating anticonvulsants, the genetics revolution of the 1990's led to the discovery of a number of single gene mutations that cause seizures, giving hope that unprecedented insight into molecular mechanisms of epilepsy is just around the corner. Still, the jump to humans is made with circumspection. Without more information about the seizure disorders caused by these genes and how they relate to humans, one is wary about investing in them if they represent only a few percent of all genes that can cause seizures. Moreover, the ascertainment of many mutants was narrow, and only a few have been subjected to (or are suitable for) proper neuropharmacological evaluation. We will develop tools to systematically screen for better mouse models of idiopathic epilepsy and to standardize characterization of extant models. The electro- and chemo-convulsive threshold tests for screening anticonvulsants are ideally suited as they are robust, are portable between laboratories and can accomodate various experimental modalities. Our focus is on single gene models, but exploits natural mouse strain variation in seizure threshold to get the most out of each. We will first evaluate four electrostimulation paradigms for high-throughput screens, and relate these to drug responses in different strains and in mutants. A minimal series of lower throughput follow-up tests will then be deployed, after which informed priorities for further study of a mutant can be made. Our hope is that such tools will deliver several new relevant idiopathic epilepsy models per year, and foster wider use of informative, characterization standards. The identification of mutants with altered neuroexcitability has added value in enriching for other neurobehavioral abnormalities that are difficult to detect in high-throughput screens.
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