Mechanisms of Valproic Acid-Induced Neurodevelopmental and Behavioral Defects

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DESCRIPTION (provided by applicant): The proper development of the nervous system during early pregnancy is particularly vulnerable to both environmental toxins and the effects of inherited genetic factors which can lead to errors in connectivity in the postnatal brain. Valproic acid (VPA) is an antiepileptic and mood stabilizing drug that, when administered during pregnancy, causes neurodevelopmental defects such as behavioral and cognitive dysfunction, including maladaptations observed in children with autism spectrum disorder and intellectual delay. The severity of effects appears to be dependent upon gestational time of maternal exposure. VPA is a histone deacetylase inhibitor, suggesting that it interferes with gene expression by an epigenetic mechanism. We have observed that administration of VPA to pregnant mice during early gestation increases the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin that acts as a critical modulator of neurogenesis in the fetal brain. This has led to the working hypothesis for this proposal: epigenetic stimulation of BDNF expression by VPA during fetal brain development causes defective forebrain neurogenesis and behavioral deficits. This hypothesis will be tested by determining 1) the extent to which VPA-induced stimulation of BDNF expression is mediated by DNA methylation and/or covalent histone modification at specific BDNF gene promoters; 2) the extent to which the proportions of cortical pyramidal neurons and GABAergic interneurons are altered by embryonic exposure to VPA; and 3) the role of altered BDNF signaling, through the trkB receptor, in mediating the effects of VPA on embryonic forebrain neurogenesis and cognition. This will be accomplished utilizing a novel transgenic mouse with a mutant trkB receptor, engineered to be selectively and reversibly blocked by administration of an exogenous antagonist. The prediction for the latter experiments is that VPA will fail to induce neurogenetic defects and abnormal behavior when the BDNF signaling pathway is inhibited. The goal of this research is to determine the mechanism by which fetal exposure to a clinically used agent, VPA, induces neurodevelopmental defects. This would enable the identification of signaling pathways that can be targeted to avoid adverse neurodevelopmental effects in pregnant women who require VPA for control of epilepsy and bipolar disorder. In addition, the project seeks to establish a paradig that would enable systematic investigation of the mechanisms by which environmental agents affect brain development as well as how environmental and genetic factors might interact to cause autism and other neurodevelopmental disorders.