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Metabolic Brain Disease

, Volume 28, Issue 4, pp 667–676 | Cite as

Expression of autophagy and UPR genes in the developing brain during ethanol-sensitive and resistant periods

  • Alexander Alimov
  • Haiping Wang
  • Mei Liu
  • Jacqueline A. Frank
  • Mei Xu
  • Xiaoming Ou
  • Jia LuoEmail author
Original Paper

Abstract

Fetal alcohol spectrum disorders (FASD) results from ethanol exposure to the developing fetus and is the leading cause of mental retardation. FASD is associated with a broad range of neurobehavioral deficits which may be mediated by ethanol-induced neurodegeneration in the developing brain. An immature brain is more susceptible to ethanol neurotoxicity. We hypothesize that the enhanced sensitivity of the immature brain to ethanol is due to a limited capacity to alleviate cellular stress. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that subcutaneous injection of ethanol induced a wide-spread neuroapoptosis in postnatal day 4 (PD4) C57BL/6 mice, but had little effect on the brain of PD12 mice. We analyzed the expression profile of genes regulating apoptosis, and the pathways of ER stress response (also known as unfolded protein response, UPR) and autophagy during these ethanol-sensitive and resistant periods (PD4 versus PD12) using PCR microarray. The expression of pro-apoptotic genes, such as caspase-3, was much higher on PD4 than PD12; in contrast, the expression of genes that regulate UPR and autophagy, such as atf6, atg4, atg9, atg10, beclin1, bnip3, cebpb, ctsb, ctsd, ctss, grp78, ire1α, lamp, lc3 perk, pik3c3, and sqstm1 was significantly higher on PD12 than PD4. These results suggest that the vulnerability of the immature brain to ethanol could result from high expression of pro-apoptotic proteins and a deficiency in the stress responsive system, such as UPR and autophagy.

Keywords

Alcohol Brain development Fetal alcohol syndrome Gene expression Neurodegeneration 

Notes

Acknowledgments

This work was supported by grants from the National Institutes of Health (AA015407 and AA019693).

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Alexander Alimov
    • 1
  • Haiping Wang
    • 1
  • Mei Liu
    • 2
  • Jacqueline A. Frank
    • 1
  • Mei Xu
    • 1
  • Xiaoming Ou
    • 3
  • Jia Luo
    • 1
    Email author
  1. 1.Department of Molecular and Biochemical PharmacologyUniversity of Kentucky College of MedicineLexingtonUSA
  2. 2.Department of Anatomy and NeurobiologyUniversity of Kentucky College of MedicineLexingtonUSA
  3. 3.Department of Psychiatry and Human BehaviorUniversity of Mississippi Medical CenterJacksonUSA

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