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Review
. 2014 Nov 11:2:123.
doi: 10.3389/fped.2014.00123. eCollection 2014.

Glia and neurodevelopment: focus on fetal alcohol spectrum disorders

Marina Guizzetti  1 , Xiaolu Zhang  2 , Calla Goeke  2 , David P Gavin  2
Affiliations
Review

Glia and neurodevelopment: focus on fetal alcohol spectrum disorders

Marina Guizzetti et al. Front Pediatr. .

Erratum in

Abstract

During the last 20 years, new and exciting roles for glial cells in brain development have been described. Moreover, several recent studies implicated glial cells in the pathogenesis of neurodevelopmental disorders including Down syndrome, Fragile X syndrome, Rett Syndrome, Autism Spectrum Disorders, and Fetal Alcohol Spectrum Disorders (FASD). Abnormalities in glial cell development and proliferation and increased glial cell apoptosis contribute to the adverse effects of ethanol on the developing brain and it is becoming apparent that the effects of fetal alcohol are due, at least in part, to effects on glial cells affecting their ability to modulate neuronal development and function. The three major classes of glial cells, astrocytes, oligodendrocytes, and microglia as well as their precursors are affected by ethanol during brain development. Alterations in glial cell functions by ethanol dramatically affect neuronal development, survival, and function and ultimately impair the development of the proper brain architecture and connectivity. For instance, ethanol inhibits astrocyte-mediated neuritogenesis and oligodendrocyte development, survival and myelination; furthermore, ethanol induces microglia activation and oxidative stress leading to the exacerbation of ethanol-induced neuronal cell death. This review article describes the most significant recent findings pertaining the effects of ethanol on glial cells and their significance in the pathophysiology of FASD and other neurodevelopmental disorders.

Keywords: astrocytes; fetal alcohol spectrum disorders; glia; microglia; neurodevelopment; oligodendrocytes.

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Figures

Figure 1
Figure 1
Enzymatic reactions catalyzed by PLD. PLD is associated with membrane receptors including G-protein coupled receptors (GPCR), receptor tyrosine kinases, or integrins, which all activate PLD. Shown is GPCR-coupled PLD, which, upon activation under physiological conditions, hydrolyzes phosphatidylcholine (PC) to produce choline and phosphatidic acid (PA), a lipid second messenger that binds and activates several signaling molecules including RAF, Akt, mTOR, and p70S6K and stimulates several cell functions including proliferation, cell trafficking, and cell survival. The PLD signaling pathway is disrupted by ethanol, which competes with water leading to the formation of phosphatidylethanol (PEth) at the expenses of phosphatidic acid, therefore, inhibiting phosphatidic acid-activated signaling and functions.
Figure 2
Figure 2
(A–C) Ethanol-treated astrocytes inhibits hippocampal neuron neurite outgrowth. Hippocampal neurons plated on top of ethanol-pre-treated astrocytes (75 mM) display reduced neurite outgrowth. Shown are representative fields (20×) of neurons incubated with control (A) and ethanol-treated (B) astrocytes; insets show the same fields at a lower magnification (10×). (C) Quantification of the length of the longest neurite and of minor neurite in 60 cells per treatment was carried out using the software Image J. ***p < 0.001, Student’s t test. (D–F) Neonatal ethanol exposure inhibits dendrite outgrowth in PD9 rats. Male rat pups were intubated with 5 g/kg ethanol or were sham (control) intubated from PD4 to PD9 and sacrificed on PD9. The brains were stained using the Golgi-Cox procedure. Representative CA1 neurons in control (D) and ethanol-exposed rats (E) are shown (10×); insets show the same fields at a lower magnification (4×). Dendrite length was measured using the software Neurolucida (F). ***p < 0.001 by Student’s t test. (G–I) Neonatal ethanol exposure reduces dendrite length in PD36 rats. Female rat pups were intubated with 5 g/kg/day of ethanol or were sham (control) intubated from PD4 to PD9 and sacrificed on PD36. Brains were stained using the Golgi-Cox procedure. Shown are representative CA1 hippocampal neurons in control (G) and ethanol-exposed rats (H) (10×); insets show the same fields at a lower magnification (4×). Dendrite length was measured using the software Neurolucida (I). **p < 0.01, Student’s t test.
Figure 3
Figure 3
Model for interactions of astrocytes and neurons in cholesterol clearance and dysregulation by ethanol. (A) Cholesterol is produced by both astrocytes and neurons. Astrocytes produce and release nascent, lipid-poor lipoproteins through the lipidation of apoE via the membrane-bound ABCA1. In the brain parenchyma, nascent lipoproteins stimulate cholesterol efflux through their interaction with ABCA1 and ABCG1 in astrocytes and ABCG4 in neurons. Lipoprotein-associated cholesterol exits the brain through the cerebrospinal fluid. (B) Ethanol upregulates ABCA1 and ABCG1 in astrocytes, and increases the formation of astrocyte lipoproteins, which extract more cholesterol from astrocytes and neurons (pathways upregulated by ethanol are in red). Neurons are sensitive to changes in cholesterol content and, upon protracted induction of cholesterol efflux, decrease their cholesterol content and undergo cell death. Chol, cholesterol.
Figure 4
Figure 4
Representation of the main effects exerted by ethanol on astrocytes, oligodendrocytes, and microglia that may play a role in the neuropathology of FASD.
See this image and copyright information in PMC

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