Maternal alcohol consumption during pregnancy can cause serious birth defects, of which fetal alcohol syndrome (FAS) is the most devastating. Recognized by characteristic craniofacial abnormalities and growth deficiency, this condition includes severe alcohol-induced damage to the developing brain. FAS children experience deficits in intellectual functioning; difficulties in learning, memory, problem solving, and attention; difficulties with mental health and social interactions. The long-term goal of present proposal is to elucidate the cellular and molecular mechanisms underlying alcohol-induced malformation of brain. Specially, we will focus on the effects of alcohol on neuronal cell migration in the developing brain, since many ectopic neurons are found in the brain of FAS patients, suggesting that alcohol exposure causes abnormal migration of immature neurons. To this end, we use cerebellum as a model system, because the effect of alcohol on brain growth is especially marked in the cerebellum. We will determine the effects of alcohol on the cerebellar granule cell migration. First, we will determine when, where and how alcohol alters the migration of cerebellar granule cells in a real-time manner with the use of acute cerebellar slice preparations and microexplant cultures. In particularly, we will examine a relationship between mounts and durations of alcohol administration and inhibition of cell movement. Second, we will determine whether changes in intracellular Ca2+ fluctuations and membrane potential of migrating granule cells are involved in alcohol-induced alteration of neuronal migration. Third, we will determine whether manipulations of intracellular Ca2+ fluctuations and membrane potentials by activating NMDA receptor or inhibiting K+ channel activity can overcome the alcohol-induced changes in cell migration. The fundamental mechanisms whereby ethanol administration leads to the disturbances of brain development have not been delineated definitively. Answers to the questions raised in this project will provide a new insight for understanding how prenatal and early postnatal exposure to alcohol causes malformation of brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013613-04
Application #
6891857
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Foudin, Laurie L
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$267,750
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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