Behavioral, neurochemical, and neuroimmune changes in Nrf2 knockout mice following early postnatal exposure to valproic acid

In the present study, two agents known to exert neurotoxic effects through the generation of reactive oxygen species were administered to genetically-altered mice lacking the Nrf2 gene. Nrf2 is a transcription factor that induces genes that protect against oxidative stress and Nrf2 knockout mice have been shown to be more sensitive to oxidative stress. The first agent, valproic acid, is a GABA (gamma amino butyric acid) agonist known to cause behavioral deficits and damage to the hippocampus and cerebellum in rodents when administered on postnatal day 14, a time when behavioral skills are first maturing. The second, amphetamine, is a stimulant that induces dopamine release leading to oxidative stress with long-term effects of dopamine depletion and cell death. In prior studies, it was shown that early exposure to one toxicant leads to increased sensitivity to other toxicants. Accordingly, in these studies, Nrf2 knockout mice were exposed to valproic acid early in life and treated with amphetamine as adults. It was found that Nrf2 knockout mice were more sensitive to the toxic effects of valproic acid in development as seen through the open field activity test, rotorod, and Morris water maze. In addition, valproic acid-treated mice were found to be less social in the social chambers during adulthood. No differences were found in dopamine depletion between genotypes and postnatal day 14 pretreatment; all mice exposed to amphetamine had lower concentrations of dopamine compared to saline-treated counterparts. In conclusion, it appears that Nrf2 knockout mice are more sensitive to the behavioral toxicity cause by valproic acid during development but did not show enhanced sensitivity to amphetamine as adults. The Nrf2 knockout mice appear to be an excellent model to assess the effects of oxidative stress inducing neurotoxicants on behavioral development.Ph. D.Includes bibliographical referencesIncludes vitaby Melody A. Furnar