Fetal alcohol effects and fetal alcohol syndrome account for a large percentage of metal retardation and behavioral disorders in the United States and impose a tremendous personal and social burden. Understanding how the immature nervous system responds to ethanol is critical to rational intervention strategies. Electrical activity promotes survival of central nervous system (CNS) neurons in vitro and in vivo and prevents natural cell death (NCD) in neurons from many CNS regions. Ethanol depresses CNS electrical activity through interactions with both N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) postsynaptic receptors. Thus it is possible that ethanol enhances developmental NCD. Recent evidence suggests that ethanol exposure is indeed toxic to immature neurons of the forebrain in vivo. The pattern of cell loss is similar to that produced by a combination of glutamate receptor blockade and GABA receptor potentiation. Our evidence suggests that immature hippocampal neurons in vitro are also susceptible to ethanol- induced cell loss, suggesting that susceptibility is intrinsic to neuronal populations affected and that ethanol itself, rather than associated metabolic or nutritional variables, induces the neuronal loss. Hippocampal neurons in culture also die when chronically exposed to GABAmimetics or NMDA receptor blockade. Cell death elicited by all three treatments is prevented by chronically depolarizing neurons. Thus, we have an in vitro model of ethanol-induced neuronal death that will allow us to explore mechanistic questions. We will examine the ultrastructural and biochemical profile of ethanol-induced hippocampal neuronal death in vitro. We will determine whether the interaction of ethanol with NMDA receptors and/or GABA receptors is sufficient to explain the neuronal loss observed in vitro. We will also address whether permanent or acute decreases in calcium signaling are important in cell loss and will determine the time course over which increases in intracellular calcium provide neuroprotection against ethanol-induced cell loss. The proposed experiments should lead to a better fundamental understanding of the mechanisms by which forebrain neurons are susceptible to ethanol-induced death.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA012952-01A1
Application #
6365689
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Sorensen, Roger
Project Start
2001-09-30
Project End
2006-08-31
Budget Start
2001-09-30
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$198,790
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Conti, Alana C; Maas Jr, James W; Moulder, Krista L et al. (2009) Adenylyl cyclases 1 and 8 initiate a presynaptic homeostatic response to ethanol treatment. PLoS One 4:e5697
Eisenman, Lawrence N; Shu, Hong-Jin; Wang, Cunde et al. (2009) NMDA potentiation by visible light in the presence of a fluorescent neurosteroid analogue. J Physiol 587:2937-47
Mennerick, Steven; Lamberta, Michael; Shu, Hong-Jin et al. (2008) Effects on membrane capacitance of steroids with antagonist properties at GABAA receptors. Biophys J 95:176-85
Akk, Gustav; Covey, Douglas F; Evers, Alex S et al. (2007) Mechanisms of neurosteroid interactions with GABA(A) receptors. Pharmacol Ther 116:35-57
Shu, H-J; Zeng, C-M; Wang, C et al. (2007) Cyclodextrins sequester neuroactive steroids and differentiate mechanisms that rate limit steroid actions. Br J Pharmacol 150:164-75
Kelley, Stephen P; Alan, Jamie K; O'Buckley, Todd K et al. (2007) Antagonism of neurosteroid modulation of native gamma-aminobutyric acid receptors by (3alpha,5alpha)-17-phenylandrost-16-en-3-ol. Eur J Pharmacol 572:94-101
Li, Ping; Shu, Hong-Jin; Wang, Cunde et al. (2007) Neurosteroid migration to intracellular compartments reduces steroid concentration in the membrane and diminishes GABA-A receptor potentiation. J Physiol 584:789-800
Eisenman, Lawrence N; Shu, Hong-Jin; Akk, Gustav et al. (2007) Anticonvulsant and anesthetic effects of a fluorescent neurosteroid analog activated by visible light. Nat Neurosci 10:523-30
Moulder, Krista L; Mennerick, Steven (2006) Synaptic vesicles: turning reluctance into action. Neuroscientist 12:11-5
Moulder, Krista L; Jiang, Xiaoping; Taylor, Amanda A et al. (2006) Physiological activity depresses synaptic function through an effect on vesicle priming. J Neurosci 26:6618-26

Showing the most recent 10 out of 28 publications