This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prenatal alcohol exposure can disrupt normal development of brain leading to profound cognitive and behavioral dysfunction including hyperactivity, learning disability, attention problems, autism and depression in children. Normal brain development depends on the guided migration of neurons along specific pathways to their appropriate targets. Most immature neurons migrate along a radial glial fiber scaffold. Suboptimal neuronal migration induced by alcohol has been implicated as a mechanism for central nervous system dysfunction leading to neurobehavioral problems. In children, brains exposed to alcohol during gestation contain clusters of neurons abnormally distributed throughout the depth of cortex. Prenatal exposure to alcohol also alters neuronal migration in animal models. Heterodimeric integrin receptors each containing an alpha and a beta subunit, mediate cell-cell and cell-extracellular matrix interactions, and cell migration in the developing brains. Cell adhesion molecules critical to neuronal migrations are now known to interact with integrin subunits and to be controlled by intracellular signals elicited by integrins. Therefore, interference with integrin function in neurons and/or surrounding cells would disrupt neuronal migration. We hypothesize that poor neuronal migration in alcohol-exposed fetuses is due to altered co-ordination amongst different integrin receptors and signals transduced by integrins. Studying effects of maternal alcohol consumption on the expression of integrin subunits and their relative contribution in the migration of neurons isolated from fetal brains may allow understanding the mechanisms of prenatal alcohol-mediated fetal brain malformations. In the proposed investigation, pregnant rats will be exposed to alcohol by regimens known to interfere with neuronal migration in fetal brains. Expression of integrin subunits that interact with laminin will be examined in normal and alcohol-exposed embryonic rat cerebral hemispheres during gestation days 18 and 20 when majority of neurons migrate. Effects of prenatal alcohol-exposure on the migration rates of dissociated neurons isolated from the fetal cerebral hemispheres will be examined using an extra cellular matrix-coated glass fiber assay. Antibodies against integrin subunits known to be involved in the neuronal migration will be applied during glass fiber assay to assess relative contribution of each integrin subunit in the migration of cerebral cortical neurons from control and alcohol-exposed fetuses. Results from this study will identify integrin subunits and their possible heterdimers that are most crucial in the migration of cortical neurons in gestation days 18 and 20 rat cerebral hemispheres and are targets of prenatal alcohol.
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