Elizabeth M. Powell - US grants

DESCRIPTION Normal development of the cerebral cortex, including the formation of appropriate corticothalamic projects is required for higher sensory and cognitive functions. One would predict that interference in the normal development of these pathways could result in, for example, cognitive defects observed in many congenital birth defects affecting the central nervous system. Furthermore, there is increasing evidence that developmental defects may even underlie disorders that are first manifested later in life. These studies focus on defining how the absence or over-expression of hepatocyte growth factor during development affects the subsequent assembly of normal circuits within the forebrain. The ability to generate animals with abnormal corticothalamic circuits will, in the future, provide models to test how modest defects at the molecular level can lead to long-term abnormalities. Furthermore, an understanding of development mechanisms can be used in the re- establishment of connections after injury.

[unreadable] DESCRIPTION (provided by applicant): Neuronal development in the central nervous system is the summation of multiple processes including cellular proliferation, migration, and differentiation. The hepatocyte growth factor/scatter factor (HGF/SF) signaling system via its receptor, MET, possesses multiple activities in cellular proliferation, migration, differentiation and survival. Initial studies demonstrated HGF/SF as a key molecule for cellular migration in the ventral forebrain. New data suggest a role in cell proliferation or survival. Genetically altered mice with reduced HGF/SF-MET signaling levels demonstrate reduced numbers of striatal GABA+ neurons and abnormal behavior. The behavioral phenotype is similar to observations from children afflicted fetal alcohol syndrome, including anxiety, social dysfunction and seizure disorders. Alcohol downregulates HGF/SF levels in many tissues, and exogenous HGF/SF can rescue the signaling deficits. These data suggest that the HGF/SF-MET system is an excellent model for defining the molecular mechanisms underlying the fetal response to alcohol exposure. We will examine the role of the HGF/SF-MET system in three aims: In Aim 1, we will define the role of HGF/SF in cell proliferation and survival. In Aim 2, we will investigate the specific actions of HGF/SF-MET system on migrating postmitotic cells. In Aim 3, we will determine how loss of HGF/SF responsiveness alters phenotypic expression of GABAergic markers. Defining the molecular mechanisms involved in the development of limbic structures is critical to our understanding of the behavioral and neurochemical alterations that result from prenatal drug exposure. [unreadable] [unreadable] [unreadable]

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. PUBLIC HEALTH RELEVANCE: Valproic acid (VPA), a widely-used antiepileptic and mood stabilizing drug, causes neurodevelopmental defects in children of women exposed during pregnancy. Based on novel preliminary results generated by the PIs, it is postulated that VPA stimulates the expression of the neurotrophin, brain-derived neurotrophic factor (BDNF), by epigenetic desilencing of the BDNF gene, leading to defective brain development and consequently abnormal behavior. Successful completion of this project would lead to identification of signaling pathways that can be targeted to avoid adverse neurodevelopmental effects in children of mothers for whom VPA is the only treatment option for controlling epilepsy and bipolar disorder.