The genetics of sound induced seizure in inbred mice.

Abstract

USCEPTIBILITY to audiogenic seizure in mice (HALL 1947; MILLER, GINSBURG and POTAS 1952) and rats (MAIER and GLASER 1940; MAIER 1943) has been shown to depend on the genotype of the animal. Different investigators have suggested different modes of inheritance for sound induced seizure including single-gene ( WITT and HALL 1949), two-gene ( GINSBURG and MILLER 1963) and polygenic modes of inheritance (FULLER and THOMPSON 1960). SCHLESINGER, BOGGAN and FREEDMAN (1965) have suggested that some of these discrepancies may depend on the particular phenotype used as an index of seizure, i.e., whether wild running, clonic, o r tonic seizures are used as indices. Another variable that could determine the outcome of such analyses is the exact age of the animal at the time of the seizure test, since age is known to be a major factor in determining susceptibility within a genotype (FULLER 1962; SCHLESINGER et al. 1965). The purpose of the experiments reported here is to investigate further the mode of inheritance of susceptibility to audiogenic seizure, using statistical methods developed by ELSTON (1966) and paying close attention to these two variables, i.e., to the phenotype used as an index and to the age of the animals. HUFF and HUFF (1962) and HUFF and FULLER (1964) have suggested that the dilute gene ( d ) might be involved in determining susceptibility to audiogenic seizure in the mouse. COLEMAN (1960) has postulated a mechanism that might account for the effects of the d locus on audiogenic seizures: dilute strains of mice are deficient in phenylalanine hydroxylase activity and excrete abnormal phenylalanine metabolites such as phenylacetic acid. Since phenylacetic acid inhibits decarboxylating reactions ( SANDLER and CLOSE 1959; HANSON 1958) d/d strains of mice might be expected to have low levels of gamma-aminobutyric acid, norepinephrine, and serotonin in the brain; and this might, in turn, account for the high incidence of seizures typically observed in these mice. SCHLESINGER et al. (1965), in an attempt to test this hypothesis, were able to show that DBA/2J mice, a d/d strain with high seizure-incidence at a certain age, had lower levels of norepinephrine and serotonin in brain than nonsusceptible mice, but only at an age which corresponded to the period of maximal seizure risk for the DBA/BJ mice. A secondary purpose of these experiments, therefore, was to test whether the d locus is indeed important in audiogenic seizure; for this purpose single-gene mutants on DBA/2J background were also used. (Breeding pairs of this mutant stock were kindly supplied by DR. E. RUSSELL, The Jackson Laboratory, Bar