Motor Function Deficits Following Chronic Prenatal Ethanol Exposure are Linked to Impairments in Insulin/IGF, Notch and Wnt Signaling in the CerebellumMing Tong2,3,5, Jason Ziplow2, William Cy Chen2,4, Quynh-Giao Nguyen2,4, Charles Kim4 and Suzanne M de la Monte1,2,3,4,5*
- *Corresponding Author:
- Suzanne M de la Monte
Pierre Galletti Research Building
Rhode Island Hospital
55 Claverick Street
Room 419, Providence
RI 02903, USA
E-mail: [email protected]
Received date: October 28, 2012; Accepted date: December 19, 2012; Published date: December 24, 2012
Citation: Tong M, Ziplow J, Chen WC, Nguyen QG, Kim C, et al. (2013) Motor Function Deficits Following Chronic Prenatal Ethanol Exposure are Linked to Impairments in Insulin/IGF, Notch and Wnt Signaling in the Cerebellum. J Diabetes Metab 4:238. doi:10.4172/2155-6156.1000238
Copyright: © 2013 Tong M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Background: Fetal alcohol spectrum disorder (FASD) is associated with deficits in cerebellar function that can persist through adolescence. Previous studies demonstrated striking inhibition of insulin and insulin-like growth factor (IGF) signaling in ethanol-exposed cerebella.
Objectives: We sought to determine if FASD-induced impairments in motor function were associated with deficits in insulin/IGF signaling in juvenile cerebella. Given the growing evidence that insulin/IGF pathways crosstalk with Notch and Wnt to promote brain development and maturation; we also examined the integrity of canonical Wnt and Notch signaling networks in the brain following chronic prenatal ethanol exposure.
Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 24% ethanol by caloric content from gestation day 6 through delivery. Pups were subjected to rotarod testing on postnatal days (P) 15-16 and sacrificed on P30. Cerebella were used for molecular and biochemical analysis of insulin/IGF-1, canonical Wnt, and Notch signaling mechanisms.
Results: Prenatal ethanol exposures impaired rotarod performance, inhibited signaling through insulin and IGF- 1 receptors, IRS-1, and Akt, increased activation of GSK-3β, and broadly suppressed genes mediating the canonical Wnt and Notch networks.
Conclusions: Abnormalities in cerebellar function following chronic prenatal ethanol exposure are associated with inhibition of insulin/IGF, canonical Wnt, and Notch networks that cross-talk via GSK-3β. Effective therapeutic measures for FASD may require multi-pronged support of interrelated signaling networks that regulate brain development.