Prenatal ethanol exposure impairs insulin and IGF signaling, which leads to cognitive/motor deficits. One main effect of developmental ethanol exposure is impaired neuronal migration. AAH is needed for neuronal migration, as it cross-talks with Notch and Wnt. Cerebellar AAH expression and function are impaired by alcohol exposure. We hypothesize that these effects are mediated by increased activation of GSK-3P, with attendant increased phosphorylation and degradation of AAH protein. We propose to: 1) characterize GSK-3P-mediated phosphorylation of AAH, and examine the effects in relation to AAH protein expression and catalytic activity, and neuronal migration;2) delineate mechanisms of ethanol-impaired AAH expression;and 3) assess the roles of ethanol and GSK-3P mediated phosphorylation of AAH in relation to Notch signaling. Validation studies will determine the degrees to which intracerebral delivery of wildtype or mutated AAH plasmids normalize cerebellar neuronal migration in ethanol-exposed rats. Measurements will include cerebellar morphometric, motor function, assays of AAH expression and catalytic activity, and analysis of insulin/IGF, Notch, and Wnt signaling networks. We also will determine if oxidative stress and anti-oxidant treatments alter AAH expression, function, and phosphorylation. For chronic prenatal ethanol exposures, we will feed pregnant Long Evans rats isocaloric control or ethanol-containing liquid diets. For binge exposures, we will bolus treat rat pups with ethanol by i.p. injection or gavage between postnatal days 1 and 10. Subsets in each group will be treated by intracerebral injection of recombinant AAH plasmid or empty vector (control). Cerebella will be used to generate precision-cut slice cultures for in vitro analysis of insulin responsiveness. Alternatively, we will measure long-term effects of the various treatments on motor coordination, cerebellar structure, insulin/IGF-1, Notch, and Wnt signaling, and AAH expression, and sacrifice the offspring on postnatal day 35 (early adolescence) or 65 (late adolescence). We expect that inhibition of GSK-SP and enhanced expression of AAH in the developing brain will prevent long-term structural and functional abnormalities caused by prenatal or early postnatal ethanol exposures.

Public Health Relevance

Prenatal alcohol exposure is the leading preventable cause of developmental cognitive-motor deficits in the USA. FASD is associated with CNS malformations, including neuronal migration disorders, which contribute to motor deficits. The proposed research will improve our understanding of how ethanol impairs neuronal migration during development and help future studies designed to prevent long-term effects of FASD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37AA011431-17S1
Application #
8923354
Study Section
Special Emphasis Panel (NSS)
Program Officer
Radaeva, Svetlana
Project Start
1996-09-30
Project End
2019-08-31
Budget Start
2014-09-10
Budget End
2015-08-31
Support Year
17
Fiscal Year
2014
Total Cost
$51,907
Indirect Cost
$19,261
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
de la Monte, Suzanne M; Tong, Ming (2014) Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem Pharmacol 88:548-59
Tong, Ming; Longato, Lisa; Ramirez, Teresa et al. (2014) Therapeutic reversal of chronic alcohol-related steatohepatitis with the ceramide inhibitor myriocin. Int J Exp Pathol 95:49-63
de la Monte, Suzanne M (2014) Relationships between diabetes and cognitive impairment. Endocrinol Metab Clin North Am 43:245-67
de la Monte, Suzanne M; Kril, Jillian J (2014) Human alcohol-related neuropathology. Acta Neuropathol 127:71-90
Derdak, Zoltan; Lang, Charles H; Villegas, Kristine A et al. (2011) Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease. J Hepatol 54:164-72
Gundogan, Fusun; Elwood, Gwen; Mark, Princess et al. (2010) Ethanol-induced oxidative stress and mitochondrial dysfunction in rat placenta: relevance to pregnancy loss. Alcohol Clin Exp Res 34:415-23
Brennan-Krohn, Thea; Salloway, Stephen; Correia, Stephen et al. (2010) Glial Vascular Degeneration in CADASIL. J Alzheimers Dis :
de la Monte, Suzanne M; Tong, Ming; Nguyen, VanAnh et al. (2010) Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. J Alzheimers Dis 21:967-84
Luu, Martin; Sabo, Edmond; de la Monte, Suzanne M et al. (2009) Prognostic value of aspartyl (asparaginyl)-beta-hydroxylase/humbug expression in non-small cell lung carcinoma. Hum Pathol 40:639-44
Tong, Ming; Dong, Matthew; de la Monte, Suzanne M (2009) Brain insulin-like growth factor and neurotrophin resistance in Parkinson's disease and dementia with Lewy bodies: potential role of manganese neurotoxicity. J Alzheimers Dis 16:585-99

Showing the most recent 10 out of 13 publications