Mechanisms of Valproic Acid-Induced Neurodevelopmental and Behavioral Defects

Summary

Principal Investigator: Elizabeth M Powell
Abstract: 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.
Funding Period: 2012-03-01 - 2017-02-28
more information: NIH RePORT

Top Publications

  1. ncbi An in vivo analysis of hematopoietic stem cell potential: hematopoietic origin of cardiac valve interstitial cells
    Richard P Visconti
    Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425, USA
    Circ Res 98:690-6. 2006
  2. ncbi Comparative in vitro study of bileaflet and tilting disk valve behavior in the pulmonary position
    Jeffrey Gohean
    Department of Mechanical Engineering and Bioengineering, Clemson University, Clemson, SC 29634 0921, USA
    J Biomech Eng 128:631-5. 2006
  3. pmc In vitro study of flow regulation for pulmonary insufficiency
    T A Camp
    Departments of Mechanical Engineering and Bioengineering, Clemson University, Clemson, SC 29631, USA
    J Biomech Eng 129:284-8. 2007
  4. ncbi Transitions in early embryonic atrioventricular valvular function correspond with changes in cushion biomechanics that are predictable by tissue composition
    Jonathan T Butcher
    Department of Cell Biology and Anatomy, Cardiovascular Developmental Biology Center, Children s Research Institute, Medical University of South Carolina, Charleston, SC, USA
    Circ Res 100:1503-11. 2007
  5. pmc Increased BDNF expression in fetal brain in the valproic acid model of autism
    Luis E F Almeida
    Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Mol Cell Neurosci 59:57-62. 2014

Research Grants

  1. NEUROGENETIC PROCESSES IN THE FETAL BRAIN
    Pasko Rakic; Fiscal Year: 2013
  2. Morphogenesis and function of the cerebral cortex
    Flora M Vaccarino; Fiscal Year: 2013

Detail Information

Publications5

  1. ncbi An in vivo analysis of hematopoietic stem cell potential: hematopoietic origin of cardiac valve interstitial cells
    Richard P Visconti
    Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425, USA
    Circ Res 98:690-6. 2006
    ..Together, these findings demonstrate HSC contribution to the adult valve fibroblast population...
  2. ncbi Comparative in vitro study of bileaflet and tilting disk valve behavior in the pulmonary position
    Jeffrey Gohean
    Department of Mechanical Engineering and Bioengineering, Clemson University, Clemson, SC 29634 0921, USA
    J Biomech Eng 128:631-5. 2006
    ..The OTD valve fully opened and closed to a PVR value of 1.6 mmHg/L/min. At lower values, the valve did not close. Valves designed for the left heart can show aberrant behavior under normal conditions as pulmonary valves...
  3. pmc In vitro study of flow regulation for pulmonary insufficiency
    T A Camp
    Departments of Mechanical Engineering and Bioengineering, Clemson University, Clemson, SC 29631, USA
    J Biomech Eng 129:284-8. 2007
    ....
  4. ncbi Transitions in early embryonic atrioventricular valvular function correspond with changes in cushion biomechanics that are predictable by tissue composition
    Jonathan T Butcher
    Department of Cell Biology and Anatomy, Cardiovascular Developmental Biology Center, Children s Research Institute, Medical University of South Carolina, Charleston, SC, USA
    Circ Res 100:1503-11. 2007
    ..These results have important implications in valvular development, as biomechanics may play a larger role in stimulating valvulogenic events than previously thought...
  5. pmc Increased BDNF expression in fetal brain in the valproic acid model of autism
    Luis E F Almeida
    Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Mol Cell Neurosci 59:57-62. 2014
    ....

Research Grants30

  1. NEUROGENETIC PROCESSES IN THE FETAL BRAIN
    Pasko Rakic; Fiscal Year: 2013
    ..Thus, we propose to continue our investigation of cellular and molecular mechanisms of normal and abnormal cortical neurogenesis to obtain new insight into the causes of these disorders that may lead to their prevention or therapy. ..
  2. Morphogenesis and function of the cerebral cortex
    Flora M Vaccarino; Fiscal Year: 2013
    ..Both aspects may offer promising leads to correct or reverse the excitatory and inhibitory neuron imbalances that are present in the cerebral cortex of neuropsychiatric and impulse control disorders. ..