Maternal intake of ethanol (EtOH) during pregnancy is detrimental to human fetal development. Principal features of the Fetal Alcohol Syndrome (FAS), which affects offspring of alcoholic mothers, include central nervous system dysfunctions (microencephaly, mental retardation), growth deficiency and particular facial characteristics. The mechanisms(s) involved in the neurotoxic effects of EtOH during development remain elusive. In this project, we propose to test the hypothesis that the brain phosphoinositide system coupled to the muscarinic cholinergic receptors represents a likely and relevant target for the developmental neurotoxicity of EtOH. Membrane phosphoinositides which are hydrolyzed upon activation of a variety of receptors leading to changes in intracellular calcium and activation of protein kinase C, exert profound influences on nervous system functions. In particular, the muscarinic receptor-stimulated phosphoinositide metabolism appears to play a primary role in the developing nervous system. Preliminary in vitro and in vivo data suggest that this system is affected by EtOH in a concentration-, time-, age-, neurotransmitter- and brain region-dependent manner. Studies included in this proposal will address the hypothesis that inhibition of muscarinic receptor-stimulated phosphoinositide metabolism is correlated with EtOH-induced microencephaly in a dose- and age-dependent manner; that regional differences exist in the effects of EtOH, and that these are related to the subtype of muscarinic receptor present and its coupling to inositol metabolism; that the effect of EtOH is due to its interaction with the coupling of muscarinic receptors with phospholipase C; and that this action will lead to a diminished ability of acetylcholine to mobilize intracellular calcium. It is expected that these studies will provide information relevant for gaining a better understanding of a potentially relevant target for the neurotoxicity of EtOH as well as the molecular features of phosphoinositide metabolism in the developing brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA008154-03
Application #
3112124
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1991-09-27
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Public Health
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Roqué, Pamela J; Guizzetti, Marina; Costa, Lucio G (2014) Synaptic structure quantification in cultured neurons. Curr Protoc Toxicol 60:12.22.1-32
Guizzetti, Marina; Kavanagh, Terrance J; Costa, Lucio G (2011) Measurements of astrocyte proliferation. Methods Mol Biol 758:349-59
Guizzetti, Marina; Moore, Nadia H; VanDeMark, Kathryn L et al. (2011) Muscarinic receptor-activated signal transduction pathways involved in the neuritogenic effect of astrocytes in hippocampal neurons. Eur J Pharmacol 659:102-7
Giordano, Gennaro; Guizzetti, Marina; Dao, Khoi et al. (2011) Ethanol impairs muscarinic receptor-induced neuritogenesis in rat hippocampal slices: Role of astrocytes and extracellular matrix proteins. Biochem Pharmacol 82:1792-9
Guizzetti, Marina; Moore, Nadia H; Giordano, Gennaro et al. (2010) Ethanol inhibits neuritogenesis induced by astrocyte muscarinic receptors. Glia 58:1395-406
Moore, Nadia H; Costa, Lucio G; Shaffer, Scott A et al. (2009) Shotgun proteomics implicates extracellular matrix proteins and protease systems in neuronal development induced by astrocyte cholinergic stimulation. J Neurochem 108:891-908
VanDeMark, Kathryn L; Guizzetti, Marina; Giordano, Gennaro et al. (2009) The activation of M1 muscarinic receptor signaling induces neuronal differentiation in pyramidal hippocampal neurons. J Pharmacol Exp Ther 329:532-42
VanDemark, Kathryn L; Guizzetti, Marina; Giordano, Gennaro et al. (2009) Ethanol inhibits muscarinic receptor-induced axonal growth in rat hippocampal neurons. Alcohol Clin Exp Res 33:1945-55
Guizzetti, Marina; Moore, Nadia H; Giordano, Gennaro et al. (2008) Modulation of neuritogenesis by astrocyte muscarinic receptors. J Biol Chem 283:31884-97
Guizzetti, M; Costa, L G (2007) Cholesterol homeostasis in the developing brain: a possible new target for ethanol. Hum Exp Toxicol 26:355-60

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