Detecting genes in new and old mouse models for epilepsy: a prospectus through the magnifying glass

Various spontaneous mutants and natural strain variants for either generali zed tonic-clonic seizures, or non-convulsive absence seizures have been des cribed in mice and rats over the years. Convulsive seizure models are usual ly ascertained by mere visual observation, while finding the less noticeabl e seizures of absence models often requires proactive screening of existing mutants with other phenotypes. To date, molecular cloning technologies has elucidated the primary basis of most of the known single locus epilepsy mu tants. Together with the 20 or so mouse knockouts with seizure-related phen otypes described to date, the frequency at which the mutants appear and div ersity of the proteins involved would suggest that 1000 or more genes can b e mutated to give rise to influence epilepsy phenotypes. As many of these g enes will cluster into molecular, cellular and developmental pathways, thei r identification may be very important for better understanding epileptic m echanisms. With this perspective, the approaches taken towards positional c loning of mouse epilepsy mutations is illustrated by comparing and contrast ing the different stages of gene identification in three different models w ith which this author has been fortunate enough to be intimately involved: slow-wave epilepsy (common gene symbol: swe, Chr 4); tottering (tg, Chr 8); and stargazer (stg, Chr 15). The comparatively sobering outlook for positi onal cloning of the more common genetically 'complex' epilepsies will also be discussed, as will more efficient new strategies for model screening and identifying the remaining 985 (or so) genes. (C) 1999 Elsevier Science B.V . All rights reserved.