NULL MUTATION OF C-FOS IMPAIRS STRUCTURAL AND FUNCTIONAL PLASTICITIESIN THE KINDLING MODEL OF EPILEPSY

It has been suggested that expression of the immediate early gene c-fo s links fleeting changes in neuronal activity to lasting modifications of neuronal structure and function in the mammalian nervous system. T o test this idea, we examined behavioral and electrophysiological indi ces of kindling development and kindling-induced sprouting of hippocam pal granule cell axons in wild-type (+/+), heterozygous (+/-), and hom ozygous (-/-) mice carrying a null mutation of c-fos. The rate of kind ling development was significantly attenuated in -/- compared with +/ mice, as evidenced by both electrophysiological and behavioral measur es. Kindling-induced granule cell axon sprouting as measured by the Ti mm stain was also attenuated in homozygous null mutants compared with +/+ mice, with an intermediate effect in +/- mice. The impairment of k indling-induced axonal sprouting in the null mutants could not be attr ibuted to either detectable loss of dentate hilar neurons or reduced a ctivation of the dentate granule cells by seizures. Instead, our data are consistent with the hypothesis that the null mutation of c-fos att enuates a pathological activity-determined functional plasticity (kind ling development) as well as a structural plasticity (messy fiber reor ganization). We favor the hypothesis that this ''fos-less phenotype'' is attributable to impaired seizure-induced transcriptional activation of one or more growth-related genes.