title: Motor Function Deficits Following Chronic Prenatal Ethanol Exposure are Linked to Impairments in Insulin/IGF, Notch and Wnt Signaling in the Cerebellum.
abstract: 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.
  
  
  OBJECTIVE
  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 cross-talk 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.
authors.affiliation: Liver Research Center, USA ; Rhode Island Hospital, USA ; Warren Alpert Medical School, Providence, RI, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.affiliation: Liver Research Center, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Ziplow
authors.affiliation: Liver Research Center, USA ; Brown University, USA.
authors.forename: William Cy
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Liver Research Center, USA ; Brown University, USA.
authors.forename: Quynh-Giao
authors.initials: QG
authors.lastname: Nguyen
authors.affiliation: Brown University, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kim
authors.affiliation: Departments of Pathology (Neuropathology), Neurology, Neurosurgery and Medicine, USA ; Liver Research Center, USA ; Rhode Island Hospital, USA ; Brown University, USA ; Warren Alpert Medical School, Providence, RI, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
keywords: Cerebellum; Fetal alcohol spectrum disorder; IGF; Insulin; Multiplex ELISA; Notch; Prenatal ethanol exposure; Signal transduction; Wnt