A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

Abstract

RationaleRodents exposed to valproic acid (VPA) in prenatal life exhibit post-natal characteristics analogous to autism spectrum disorder (ASD). Many previous studies used relatively high doses of VPA during early pregnancy, potentially confounding interpretation because the offspring are the ‘survivors’ of a toxic insult. Low dose or late gestation exposure has not been widely studied. ObjectivesWe examined the behavioral sequelae of late gestation exposure to low dose VPA in the mouse. We also examined postnatal levels of glutamic acid decarboxylase (GAD65 and GAD67) as markers for GABA neurons, because GABA pathology and subsequent excitatory/inhibitory imbalance is strongly implicated in ASD. MethodsPregnant C57BL/6N mice received a single subcutaneous injection of 100 or 200mg/kg on gestation day 17. The control group received a saline injection on the same day. The offspring were tested in a battery of behavioral tests in adolescence and adulthood. Six brain regions were harvested and GAD65 and GAD67 were measured by western blotting. ResultsCompared to saline-exposed controls, adult mice exposed to prenatal VPA had impaired novel object exploration and fear conditioning anomalies. GAD67 was decreased in midbrain, olfactory bulb, prefrontal cortex and increased in cerebellum, hippocampus and striatum; GAD65 was decreased in all 6 regions. ConclusionsOur results suggest that a low dose of VPA in late pregnancy has persistent effects on brain development, and in particular the GABA system, which may be relevant to ASD. Further attention to the impact of gestation time and dose of exposure in VPA-induced ASD models is encouraged.