Inherited convulsive disorders in mice

In this chapter, we review the major inherited convulsive disorders found in mice and discuss their possible relationship to specific clinical seizure disorders in humans. These disorders in mice include audiogenic seizures, the epilepsy (El) mouse, various spontaneous seizures, the tottering/leaner syndrome, seizures associated with cerebellar abnormalities, seizures associated with myelin disorders, and alcohol withdrawal seizures. We find that for most major types of epilepsy in humans, there exists a similar counterpart in the mouse. Because human and rodent nervous systems respond similarly to seizure-provoking stimuli, it is possible that biochemical and physiological mechanisms of naturally occurring convulsive disorders are also similar in these species. The use of recombinant inbred (RI) and congenic mouse strains for genetic and biochemical studies of audiogenic seizures is presented. Using these strains, we have identified a major gene, Ias, that inhibits the spread of seizure activity. This gene was found through its close linkage with the Ah locus on chromosome 17. We also found that juvenile-onset and adult-onset audiogenic seizures are controlled by different genetic systems. The problem of juvenile-onset audiogenic seizure susceptibility is especially interesting because these seizures are genetically associated with an ecto-Ca2+-ATPase deficiency among the RI strains. This deficiency is the first neurochemical trait found to be inherited together with an idiopathic convulsive disorder, and may represent a potentially important basic mechanism of epilepsy. Because the brains of human epileptics are generally inaccessible for neurochemical research, the epileptic mouse mutants offer a convenient means of pursuing this type of research. The well-known genetic constitution of the mouse, together with the availability of numerous physiologically distinct convulsive disorders, makes the mouse ideally suited for molecular, genetic, and biochemical studies of convulsive behavior.