Epilepsy is 1 of the most common neurological disorders. Drug therapy is effective in only 75% of all cases, and many protected individuals still suffer detrimental side effects. Although mice have traditionally been used as experimental models for epilepsy, e.g. for testing antiepileptic drugs, they can provide exceptional genetic models as well. We will continue our work on the discovery and development of new genetic models and molecular mechanisms for epilepsy. We recently adopted 3 new epileptic mutants with phenotypic features that make them particularly attractive as pre-clinical models. 2 of these have dominantly inherited limbic seizures with little or no other impairment. The first, """"""""frequent-flyer"""""""" was caused by transgene insertion at the Bruno14 locus, which encodes an RNA splicing factor which represents a new gene target for epilepsy. Although the phenotype is technically monogenic, because Bruno14 has multiple RNA targets-some of which are the 'usual suspects' for synaptic transmission and others which are novel - the model mimics a polygenic disorder. For this reason it is a very attractive model, well suited for microarray analysis, which we propose, to explore the functional association between these RNA targets and phenotypic outcome. Frequent-flyer mice also have a low seizure threshold, making them practical for genetic interaction tests which we will perform, and drug screening in the future. The """"""""fitful"""""""" mutation arose spontaneously; its limbic seizure phenotype is also dominant with late onset. Homozygotes, however, have seizures at a younger age and are runted, ataxic, have neurosensory defects, and often die before weaning. We have delimited the critical interval to 18 genes, none of which encode ion channels or other proteins previously known to be associated with epilepsy; here our aim is to identify the gene and to characterize the tractable recessive neurosensory deficits to provide clues towards the cause of the seizures. """"""""Spike-wave-1"""""""" arose in the common inbred substrain C3H/He, and interacts with alleles from wild-type mice to provide a new model for idiopathic absence epilepsy. As there are only a few genes known for absence epilepsy, and, in particular, no genetic mouse models with absence seizures that are unaccompanied by general neurological impairment, further development of this model provides new opportunities for insight into the genetic basis of absence epilepsy.
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