The Cerebellum

, Volume 11, Issue 1, pp 145–154

Mechanisms of Ethanol-Induced Death of Cerebellar Granule Cells

Article

DOI: 10.1007/s12311-010-0219-0

Cite this article as:
Luo, J. Cerebellum (2012) 11: 145. doi:10.1007/s12311-010-0219-0

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.

Keywords

ApoptosisCell signalingDevelopmentFetal alcohol exposureNeurodegenerationNeuroprotection

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

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of Kentucky College of MedicineLexingtonUSA