Ethanol impairs Rho GTPase signaling and differentiation of cerebellar granule neurons in a rodent model of fetal alcohol syndrome.
Developmental exposure to ethanol impairs fetal brain development and causes fetal alcohol syndrome. Although the cerebellum is one of the most alcohol-sensitive brain areas, signaling mechanisms underlying the deleterious effects of ethanol on developing cerebellar granule neurons (CGNs) are largely unknown. Here we describe the effects of in vivo ethanol exposure on neurite formation in CGNs and on the activation of Rho GTPases (RhoA and Rac1), regulators of neurite formation. Exposure of 7-day-old rat pups to ethanol for 3 h moderately increased blood alcohol concentration (BAC) ( approximately 40 mM) and inhibited neurite formation and Rac1 activation in CGNs. Longer exposure to ethanol for 5 h resulted in higher BAC ( approximately 80 mM), induced apoptosis, inhibited Rac1, and activated RhoA. Studies demonstrated a regulatory role of Rho GTPases in differentiation of cerebellar neurons, and indicated that ethanol-associated impairment of Rho GTPase signaling might contribute to brain defects observed in fetal alcohol syndrome.
Joshi
S
S
Department of Internal Medicine, Division of Molecular Cardiology, Cardiovascular Research and Cancer Institute, The Texas A & M University System Health Science Center, College of Medicine, College Station, TX 76504, USA.
Guleria
R S
RS
Pan
J
J
Bayless
K J
KJ
Davis
G E
GE
Dipette
D
D
Singh
U S
US
D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D002454:Cell Differentiation / Q000187:drug effects*; D002531:Cerebellum / Q000166:cytology*; D004195:Disease Models, Animal; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000431:Ethanol; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein