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Mechanisms of Ethanol-Induced Death of Cerebellar Granule Cells

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Abstract

Maternal ethanol exposure during pregnancy may cause fetal alcohol spectrum disorders (FASD). FASD is the leading cause of mental retardation. The most deleterious effect of fetal alcohol exposure is inducing neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. The cerebellum is one of the brain areas that are most susceptible to ethanol during development. Ethanol exposure causes a loss of both cerebellar Purkinje cells and granule cells. This review focuses on the toxic effect of ethanol on cerebellar granule cells (CGC) and the underlying mechanisms. Both in vitro and in vivo studies indicate that ethanol induces apoptotic death of CGC. The vulnerability of CGC to ethanol-induced death diminishes over time as neurons mature. Several mechanisms for ethanol-induced apoptosis of CGC have been suggested. These include inhibition of N-methyl-d-aspartate receptors, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, disturbance of potassium channel currents, thiamine deficiency, and disruption of translational regulation. Cultures of CGC provide an excellent system to investigate cellular/molecular mechanisms of ethanol-induced neurodegeneration and to evaluate interventional strategies. This review will also discuss the approaches leading to neuroprotection against ethanol-induced neuroapoptosis.

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Abbreviations

BAC:

Blood alcohol concentration

BDNF:

Brain-derived neurotrophic factor

CDK:

Cyclin-dependent kinase

CGC:

Cerebellar granule cells

CGCP:

CGC precursor

CNS:

Central nervous system

EGL:

External germinal layer

FASD:

Fetal alcohol spectrum disorders

IGF-I:

Insulin-like growth factor I

IGL:

Internal granule layer

ML:

Molecular layer

MMP:

Mitochondrial membrane potential

NGF:

Nerve growth factor

NMDA:

N-methyl-d-aspartate

NO:

Nitric oxide

PACAP:

Pituitary adenylate cyclase-activating polypeptide

PCL:

Purkinje cell layer

PD:

Postnatal days

PI3K:

Phosphatidylinositol 3-kinase

PKG:

Cyclic GMP-dependent protein kinase

PKR:

Double-stranded RNA-activated protein kinase

RA:

Retinoic acid

ROS:

Reactive oxygen species

TD:

Thiamine deficiency

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Acknowledgment

I would like to thank Kimberly Bower for reading this manuscript. This research was supported by grants from the National Institutes of Health (AA015407, AA019693 and AA017226).

Disclosure of potential conflicts of interest

I do not have any potential conflicts of interest for this work.

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  1. Department of Internal Medicine, University of Kentucky College of Medicine, 130 Bosomworth Health Sciences Research Building, 1095 Veterans Drive, Lexington, KY, 40536, USA

    Jia Luo

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  1. Jia Luo
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Correspondence to Jia Luo.

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Luo, J. Mechanisms of Ethanol-Induced Death of Cerebellar Granule Cells. Cerebellum 11, 145–154 (2012). https://doi.org/10.1007/s12311-010-0219-0

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  • DOI: https://doi.org/10.1007/s12311-010-0219-0

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