Valproic acid induces nuclear factor erythroid 2-related factor 2 expression in fetal and neonatal brains but not in adult brain: evidence of the gamma-aminobutyric acid-shift hypothesis.

The gamma-aminobutyric acid (GABA)-shift hypothesis proposes that GABA agonist action is excitatory early in development and transitions to an inhibitory role later in life. In experiment 1, the nonspecific GABA agonist, valproic acid (VPA), was administered to pregnant C57BL/6 mice on embryonic day 13. Fetal and maternal brains were harvested 2 h post-VPA exposure and assayed for nuclear factor erythroid 2-related factor 2 (NRF2) and H3 expression through western blot analysis. In experiment 2, VPA was administered to neonatal pups on P14 and adult mice on P60. In both experiments, it was observed that NRF2 expression was increased in fetal and neonatal brains, but not in the adult brain. Because NRF2 expression is activated by oxidative stress, these results imply support of the GABA-shift hypothesis in that VPA may exert its developmental damage in the fetal and neonatal periods through excitotoxicity.