Repression of activity-dependent c-fos and brain-derived neurotrophic factor mRNA expression by pyrethroid insecticides accompanying a decrease in Ca(2+) influx into neurons

Abstract

Permethrin, a type I pyrethroid insecticide, is known to affect sodium channels of neurons and prolong sodium currents. On the other hand, the expression of brain-derived neurotrophic factor (BDNF) and c-fos genes is activated through Ca(2+) influx into neurons, in an activity-dependent manner. In this study, therefore, we investigated whether permethrin influenced the Ca(2+) signal-induced expression of these genes. In primary culture of mouse cerebellar granule cells (CGCs), stimulation with veratridine, a potent agonist for sodium channels, which causes membrane depolarization in neurons, induced c-fos and BDNF mRNA expression accompanying the Ca(2+) influx into neurons. Pretreatment with permethrin at doses nontoxic to CGCs repressed the induction of these genes dose dependently, with trans-permethrin more potent than cis-permethrin. Consistent with this, the increase in Ca(2+) influx caused by veratridine was repressed by permethrin. The membrane depolarization induced by elevating the potassium (K(+)) concentration in medium (high K(+)) caused the activation of c-fos and BDNF genes, which was also repressed by permethrin. Immunoblotting analysis of c-Fos and a gel-mobility assay of AP-1 DNA-binding activity supported the decrease in c-Fos synthesis in permethrin-treated CGCs. The type II pyrethroid cypermethrin also affected the expression of these genes but less effectively than permethrin. Thus, pyrethroids inhibit the activity-dependent gene expression in neurons.