Maturation-dependent alcohol resistance in the developing mouse: cerebellar neuronal loss and gene expression during alcohol-vulnerable and -resistant periods

Author(s): Karaçay B, Li S, Bonthius DJ


Background: Alcohol abuse during pregnancy injures the fetal brain. One of alcohol's most important neuroteratogenic effects is neuronal loss. Rat models have shown that the cerebellum becomes less vulnerable to alcohol-induced neuronal death as it matures. We determined if maturation-dependent alcohol resistance occurs in mice and compared patterns of gene expression during the alcohol resistant and sensitive periods.

Methods: Neonatal mice received alcohol daily over postnatal day (PD) 2 to 4 or PD8 to 10. Purkinje cells and granule cells were quantified on PD25. The temporal expression patterns of 4 neuro-developmental genes and 3 neuro-protective genes in the cerebellum were determined daily over PD0 to 15 to determine how gene expression changes as the cerebellum transitions from alcohol-vulnerable to alcohol-resistant. The effect of alcohol on expression of these genes was determined when the cerebellum is alcohol sensitive (PD4) and resistant (PD10).

Results: Purkinje and granule cells were vulnerable to alcohol-induced death at PD2 to 4, but not at PD8 to 10. Acquisition of maturation-dependent alcohol resistance coincided with changes in the expression of neurodevelopmental genes. The vulnerability of cerebellar neurons to alcohol toxicity declined in parallel with decreasing levels of Math1 and Cyclin D2, markers of immature granule cells. Likewise, the rising resistance to alcohol toxicity paralleled increasing levels of GABA alpha-6 and Wnt-7a, markers of mature granule neurons. Expression of growth factors and genes with survival promoting function (IGF-1, BDNF, and cyclic AMP response element binding protein) did not rise as the cerebellum transitioned from alcohol-vulnerable to alcohol-resistant. All 3 were expressed at substantial levels during the vulnerable period and were not expressed at higher levels later. Acute alcohol exposure altered the expression of neurodevelopmental genes and growth factor genes when administered either during the alcohol vulnerable period or resistant period. However, the patterns in which gene expression changed varied among the genes and depended on timing of alcohol administration.

Conclusions: Mice have a temporal window of vulnerability in the first week of life, during which cerebellar neurons are more sensitive to alcohol toxicity than during the second week. Expression of genes governing neuronal maturation changes in synchrony with the acquisition of alcohol resistance. Growth factors do not rise as the cerebellum transitions from alcohol-vulnerable to alcohol-resistant. Thus, a process intrinsic to neuronal maturation, rather than rising levels of growth factors, likely underlies maturation-dependent alcohol resistance.

Similar Articles

Fetal alcohol spectrum disorders: an overview

Author(s): Riley EP, Infante MA, Warren KR

Regulation of neuronal survival by the serine-threonine protein kinase Akt

Author(s): Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, et al.

Ethanol inhibition of insulin signaling in hepatocellular carcinoma cells

Author(s): Banerjee K, Mohr L, Wands JR, de la Monte SM

Partial rescue of ethanol-induced neuronal apoptosis by growth factor activation of phosphoinositol-3-kinase

Author(s): de la Monte SM, Ganju N, Banerjee K, Brown NV, Luong T, et al.

Acute ethanol exposure inhibits insulin signaling in the liver

Author(s): He J, de la Monte S, Wands JR

Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver

Author(s): Yeon JE, Califano S, Xu J, Wands JR, De La Monte SM

Frizzled signaling and the developmental control of cell polarity

Author(s): Shulman JM, Perrimon N, Axelrod JD

Roles of Wnt proteins in neural development and maintenance

Author(s): Patapoutian A, Reichardt LF

Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1

Author(s): Galceran J, Miyashita-Lin EM, Devaney E, Rubenstein JL, Grosschedl R

Wnt signalling required for expansion of neural crest and CNS progenitors

Author(s): Ikeya M, Lee SM, Johnson JE, McMahon AP, Takada S

Wnt signaling regulates hepatic metabolism

Author(s): Liu H, Fergusson MM, Wu JJ, Rovira II, Liu J, et al.

Wnt signaling regulates mitochondrial physiology and insulin sensitivity

Author(s): Yoon JC, Ng A, Kim BH, Bianco A, Xavier RJ, et al.

Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1)

Author(s): Tanneberger K, Pfister AS, Kriz V, Bryja V, Schambony A, et al.

Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling

Author(s): Roberts DM, Pronobis MI, Poulton JS, Waldmann JD, Stephenson EM, et al.

Notch in the vertebrate nervous system: an old dog with new tricks

Author(s): Pierfelice T, Alberi L, Gaiano N

Notch targets and their regulation

Author(s): Bray S, Bernard F

Roles of bHLH genes in neural stem cell differentiation

Author(s): Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R

Overexpression of human aspartyl(asparaginyl)beta-hydroxylase in hepatocellular carcinoma and cholangiocarcinoma

Author(s): Lavaissiere L, Jia S, Nishiyama M, de la Monte S, Stern AM, et al.

Aspartyl-(asparaginyl)-beta-hydroxylase regulates hepatocellular carcinoma invasiveness

Author(s): de la Monte SM, Tamaki S, Cantarini MC, Ince N, Wiedmann M, et al.

Impaired placentation in fetal alcohol syndrome

Author(s): Gundogan F, Elwood G, Longato L, Tong M, Feijoo A, et al.

Role of the aspartyl-asparaginyl-beta-hydroxylase gene in neuroblastoma cell motility

Author(s): Sepe PS, Lahousse SA, Gemelli B, Chang H, Maeda T, et al.

AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis

Author(s): Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, et al.

Wnt signaling function in Alzheimer's disease

Author(s): De Ferrari GV, Inestrosa NC