Special Issue "Ethanol Neurotoxicity"

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A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (28 February 2013)

Special Issue Editor

Guest Editor
Dr. D. Blaine Moore (Website)

Department of Biology, Kalamazoo College, Kalamazoo, MI 49006, USA
Phone: +269 337 7301
Fax: +269 337 7508
Interests: ethanol toxicity mechanism; particularly the role of Bcl-2 family members and caspases

Special Issue Information

Dear Colleagues,

Alcohol abuse is a worldwide public health concern resulting in significant morbidity, mortality and financial burden. Decades of research have pinpointed the pathological consequences of ethanol and have focused considerable attention on neurotoxicity. Indeed, ethanol is known to induce structural changes and neuronal cell death in the nervous system of humans and animals, and significant progress is being made in unraveling the mechanisms and neural consequences of ethanol exposure. Several important questions related to ethanol neurotoxicity remain unanswered: What is the precise cellular mechanism of ethanol induced neuronal cell death? What is the role of support cells such as glia in neurotoxicity, and are glia themselves targets of ethanol? What are the developmental consequences of ethanol exposure culminating in Fetal Alcohol Spectrum Disorders (FASD)? How does ethanol affect neuronal membrane proteins such as receptors and transporters? Are synaptic connections between neurons affected by ethanol? What are the pathological consequences of long-term ethanol exposure in alcoholics? What structural changes are noted in brain imaging studies of chronic alcoholics or children with FASD?

This special issue will collect a series of articles which document the important strides being made towards understanding the basis for and consequences of ethanol neurotoxicity. It is meant to be inclusive of the major questions indicated above, and it is my hope that the ethanol research community will greatly benefit from this anthology.

Sincerely,
Dr. D. Blaine Moore
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 600 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • ethanol-induced neuronal apoptosis
  • fetal alcohol spectrum disorder
  • ethanol and membrane proteins
  • ethanol and signal transduction
  • ethanol and glia
  • ethanol and synapses/circuitry
  • neuropathology in chronic alcoholism
  • ethanol and neuro-imaging
  • ethanol and cognition

Published Papers (11 papers)

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Research

Jump to: Review

Open AccessArticle Developmental Neurotoxicity of Alcohol and Anesthetic Drugs Is Augmented by Co-Exposure to Caffeine
Brain Sci. 2013, 3(3), 1128-1152; doi:10.3390/brainsci3031128
Received: 22 April 2013 / Revised: 6 July 2013 / Accepted: 11 July 2013 / Published: 30 July 2013
Cited by 1 | PDF Full-text (8968 KB) | HTML Full-text | XML Full-text
Abstract
Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature [...] Read more.
Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants to stimulate respiration, and these infants are also exposed simultaneously to anesthetic drugs for procedural sedation and/or surgical procedures. Pregnant women who abuse alcohol or other apoptogenic drugs also may heavily consume CAF. We administered CAF to infant mice alone or in combination with alcohol, phencyclidine, diazepam, midazolam, ketamine, or isoflurane, which are drugs of abuse and/or drugs frequently used in pediatric medicine, and found that CAF weakly triggers neuroapoptosis by itself and markedly potentiates the neuroapoptogenic action of each of these other drugs. Exposure of infant mice to CAF + phencyclidine resulted in long-term impairment in behavioral domains relevant to attention deficit/hyperactivity disorder, whereas exposure to CAF + diazepam resulted in long-term learning/memory impairment. At doses used in these experiments, these behavioral impairments either did not occur or were substantially less pronounced in mice exposed to CAF alone or to phencyclidine or diazepam alone. CAF currently enjoys the reputation of being highly beneficial and safe for use in neonatal medicine. Our data suggest the need to consider whether CAF may have harmful as well as beneficial effects on the developing brain, and the need for research aimed at understanding the full advantage of its beneficial effects while avoiding its potentially harmful effects. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle Effects of Ethanol Exposure during Distinct Periods of Brain Development on Hippocampal Synaptic Plasticity
Brain Sci. 2013, 3(3), 1076-1094; doi:10.3390/brainsci3031076
Received: 15 May 2013 / Revised: 15 June 2013 / Accepted: 29 June 2013 / Published: 19 July 2013
Cited by 5 | PDF Full-text (349 KB) | HTML Full-text | XML Full-text
Abstract
Fetal alcohol spectrum disorders occur when a mother drinks during pregnancy and can greatly influence synaptic plasticity and cognition in the offspring. In this study we determined whether there are periods during brain development that are more susceptible to the effects of [...] Read more.
Fetal alcohol spectrum disorders occur when a mother drinks during pregnancy and can greatly influence synaptic plasticity and cognition in the offspring. In this study we determined whether there are periods during brain development that are more susceptible to the effects of ethanol exposure on hippocampal synaptic plasticity. In particular, we evaluated how the ability to elicit long-term potentiation (LTP) in the hippocampal dentate gyrus (DG) was affected in young adult rats that were exposed to ethanol during either the 1st, 2nd, or 3rd trimester equivalent. As expected, the effects of ethanol on young adult DG LTP were less severe when exposure was limited to a particular trimester equivalent when compared to exposure throughout gestation. In males, ethanol exposure during the 1st, 2nd or 3rd trimester equivalent did not significantly reduce LTP in the DG. In females, ethanol exposure during either the 1st or 2nd trimester equivalents did not impact LTP in early adulthood, but following exposure during the 3rd trimester equivalent alone, LTP was significantly increased in the female DG. These results further exemplify the disparate effects between the ability to elicit LTP in the male and female brain following perinatal ethanol exposure (PNEE). Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle Ethanol Neurotoxicity in the Developing Cerebellum: Underlying Mechanisms and Implications
Brain Sci. 2013, 3(2), 941-963; doi:10.3390/brainsci3020941
Received: 11 April 2013 / Revised: 8 May 2013 / Accepted: 4 June 2013 / Published: 14 June 2013
Cited by 8 | PDF Full-text (453 KB) | HTML Full-text | XML Full-text
Abstract
Ethanol is the main constituent of alcoholic beverages that exerts toxicity to neuronal development. Ethanol affects synaptogenesis and prevents proper brain development. In humans, synaptogenesis takes place during the third trimester of pregnancy, and in rodents this period corresponds to the initial [...] Read more.
Ethanol is the main constituent of alcoholic beverages that exerts toxicity to neuronal development. Ethanol affects synaptogenesis and prevents proper brain development. In humans, synaptogenesis takes place during the third trimester of pregnancy, and in rodents this period corresponds to the initial few weeks of postnatal development. In this period neuronal maturation and differentiation begin and neuronal cells start migrating to their ultimate destinations. Although the neuronal development of all areas of the brain is affected, the cerebellum and cerebellar neurons are more susceptible to the damaging effects of ethanol. Ethanol’s harmful effects include neuronal cell death, impaired differentiation, reduction of neuronal numbers, and weakening of neuronal plasticity. Neuronal development requires many hormones and growth factors such as retinoic acid, nerve growth factors, and cytokines. These factors regulate development and differentiation of neurons by acting through various receptors and their signaling pathways. Ethanol exposure during development impairs neuronal signaling mechanisms mediated by the N-methyl-d-aspartate (NMDA) receptors, the retinoic acid receptors, and by growth factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-I), and basic fibroblast growth factor (bFGF). In combination, these ethanol effects disrupt cellular homeostasis, reduce the survival and migration of neurons, and lead to various developmental defects in the brain. Here we review the signaling mechanisms that are required for proper neuronal development, and how these processes are impaired by ethanol resulting in harmful consequences to brain development. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle Effects of Lifelong Ethanol Consumption on Brain Monoamine Transmitters in Alcohol-Preferring Alko Alcohol (AA) Rats
Brain Sci. 2013, 3(2), 790-799; doi:10.3390/brainsci3020790
Received: 1 March 2013 / Revised: 2 May 2013 / Accepted: 7 May 2013 / Published: 15 May 2013
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Abstract
The purpose of the present study was to examine the combined effects of aging and lifelong ethanol exposure on the levels of monoamine neurotransmitters in different regions of the brain. This work is part of a project addressing interactions of aging and [...] Read more.
The purpose of the present study was to examine the combined effects of aging and lifelong ethanol exposure on the levels of monoamine neurotransmitters in different regions of the brain. This work is part of a project addressing interactions of aging and lifelong ethanol consumption in alcohol-preferring AA (Alko Alcohol) line of rats, selected for high voluntary consumption of ethanol. Intake of ethanol on the level of 4.5–5 g/kg/day for about 20 months induced only limited changes in the neurotransmitter levels; the concentration of noradrenaline was significantly reduced in the frontal cortex. There was also a trend towards lower levels of dopamine and 5-hydroxytryptamine (5-HT) in the frontal cortex, and towards a lower noradrenaline level in the dorsal cortex. Aging was associated with a decreased concentration of dopamine in the dorsal cortex and with a declining trend in the striatum. The levels of 5-HT in the limbic forebrain were higher in the aged than in the young animals, and in the striatum, there was a trend towards higher levels in older animals. The data suggest that a continuous intake of moderate amounts of ethanol does not enhance the age-related alterations in brain monoamine neurotransmission, while the decline in the brain level of dopamine associated with aging may be a factor contributing to age-related neurological disorders. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle Differential Effects of Chronic and Chronic-Intermittent Ethanol Treatment and Its Withdrawal on the Expression of miRNAs
Brain Sci. 2013, 3(2), 744-756; doi:10.3390/brainsci3020744
Received: 27 February 2013 / Revised: 11 April 2013 / Accepted: 25 April 2013 / Published: 3 May 2013
Cited by 5 | PDF Full-text (372 KB) | HTML Full-text | XML Full-text
Abstract
Chronic and excessive alcohol misuse results in changes in the expression of selected miRNAs and their mRNA targets in specific regions of the human brain. These expression changes likely underlie the cellular adaptations to long term alcohol misuse. In order to delineate [...] Read more.
Chronic and excessive alcohol misuse results in changes in the expression of selected miRNAs and their mRNA targets in specific regions of the human brain. These expression changes likely underlie the cellular adaptations to long term alcohol misuse. In order to delineate the mechanism by which these expression changes occur, we have measured the expression of six miRNAs including miR-7, miR-153, miR-152, miR-15B, miR-203 and miR-144 in HEK293T, SH SY5Y and 1321 N1 cells following exposure to ethanol. These miRNAs are predicted to target key genes involved in the pathophysiology of alcoholism. Chronic and chronic-intermittent exposure to ethanol, and its removal, resulted in specific changes in miRNA expression in each cell line suggesting that different expression patterns can be elicited with different exposure paradigms and that the mechanism of ethanol’s effects is dependent on cell type. Specifically, chronic exposure to ethanol for five days followed by a five day withdrawal period resulted in up-regulation of several miRNAs in each of these cell lines similar to expression changes identified in post mortem human brain. Thus, this model can be used to elucidate the role of miRNAs in regulating gene expression changes that occur in response to ethanol exposure. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle Ethanol Modulates Spontaneous Calcium Waves in Axonal Growth Cones in Vitro
Brain Sci. 2013, 3(2), 615-626; doi:10.3390/brainsci3020615
Received: 14 March 2013 / Revised: 12 April 2013 / Accepted: 16 April 2013 / Published: 23 April 2013
Cited by 1 | PDF Full-text (373 KB) | HTML Full-text | XML Full-text
Abstract
In developing neurons the frequency of long duration, spontaneous, transient calcium (Ca2+) elevations localized to the growth cone, is inversely related to the rate of axon elongation and increases several fold when axons pause. Here we report that these spontaneous [...] Read more.
In developing neurons the frequency of long duration, spontaneous, transient calcium (Ca2+) elevations localized to the growth cone, is inversely related to the rate of axon elongation and increases several fold when axons pause. Here we report that these spontaneous Ca2+ transients with slow kinetics, called Ca2+ waves, are modulated by conditions of ethanol exposure that alter axonal growth dynamics. Using time-series fluorescence calcium imaging we found that acute treatment of fetal rat hippocampal neurons with 43 or 87 mM ethanol at an early stage of development in culture decreased the percent of axon growth cones showing at least one Ca2+ wave during 10 min of recording, from 18% in controls to 5% in cultures exposed to ethanol. Chronic exposure to 43 mM ethanol also reduced the incidence of Ca2+ waves to 8%, but exposure to 87 mM ethanol increased their incidence to 31%. Neither chronic nor acute ethanol affected the peak amplitude, time to peak or total duration of Ca2+ waves. In some experiments, we determined the temporal correlation between Ca2+ waves and growth and non-growth phases of axonal growth dynamics. As expected, waves were most prevalent in stationary or retracting growth cones in all treatment groups, except in cultures exposed chronically to 87 mM ethanol. Thus, the relationship between growth cone Ca2+ waves and axon growth dynamics is disrupted by ethanol. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessArticle White Matter Integrity Pre- and Post Marijuana and Alcohol Initiation in Adolescence
Brain Sci. 2013, 3(1), 396-414; doi:10.3390/brainsci3010396
Received: 24 December 2012 / Revised: 5 February 2013 / Accepted: 12 March 2013 / Published: 22 March 2013
Cited by 11 | PDF Full-text (591 KB) | HTML Full-text | XML Full-text
Abstract
Characterizing the effects of alcohol and marijuana use on adolescent brain development is important for understanding potential alterations in neurodevelopment. Several cross sectional studies have identified group differences in white matter integrity after initiation of heavy alcohol and marijuana use, however none [...] Read more.
Characterizing the effects of alcohol and marijuana use on adolescent brain development is important for understanding potential alterations in neurodevelopment. Several cross sectional studies have identified group differences in white matter integrity after initiation of heavy alcohol and marijuana use, however none have explored white matter trajectories in adolescents pre- and post initiation of use, particularly for marijuana users. This study followed 16 adolescents with minimal alcohol and marijuana use at ages 16–18 over three years. At follow-up, teens were 19–22 years old; half of the participants initiated heavy alcohol use and half initiated heavy alcohol and marijuana use. Repeated-measures ANOVA revealed 20 clusters in association and projection fibers tracts (p < 0.01) in which a group by time interaction was found. Most consistently, white matter integrity (i.e., fractional anisotropy) decreased for those who initiated both heavy alcohol and marijuana use over the follow-up interval. No effect of time or change in white matter integrity was seen for those who initiated alcohol use only in the majority of clusters. In most regions, at the baseline time point, teens who would later initiate both alcohol and marijuana use demonstrated white matter integrity greater than or equal to teens that initiated alcohol use only. Findings suggest poorer tissue integrity associated with combined initiation of heavy alcohol and marijuana use in late adolescence. While pre-existing differences may also be related to likelihood of substance use, the present data suggest an effect on tissue integrity for these teens transitioning to combined alcohol and marijuana use in later adolescence. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)

Review

Jump to: Research

Open AccessReview Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs Can Disrupt Brain Development
Brain Sci. 2013, 3(3), 1153-1181; doi:10.3390/brainsci3031153
Received: 25 May 2013 / Revised: 8 July 2013 / Accepted: 11 July 2013 / Published: 31 July 2013
Cited by 7 | PDF Full-text (5703 KB) | HTML Full-text | XML Full-text
Abstract
Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol [...] Read more.
Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation) can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs) in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs) and anti-epileptics (AEDs), mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which alcohol, GAs and AEDs produce neurobehavioral deficit syndromes is by triggering apoptotic death and deletion of neurons and OLs (or their precursors) from the developing brain. Therefore, there is a need for research aimed at deciphering mechanisms by which these agents trip the apoptosis trigger, the ultimate goal being to learn how to prevent these agents from causing neurodevelopmental disabilities. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessReview Fetal Alcohol Spectrum Disorder (FASD) Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets
Brain Sci. 2013, 3(2), 964-991; doi:10.3390/brainsci3020964
Received: 1 April 2013 / Revised: 3 June 2013 / Accepted: 4 June 2013 / Published: 19 June 2013
Cited by 10 | PDF Full-text (2180 KB) | HTML Full-text | XML Full-text
Abstract
Fetal alcohol spectrum disorder (FASD), caused by prenatal alcohol exposure, can result in craniofacial dysmorphism, cognitive impairment, sensory and motor disabilities among other defects. FASD incidences are as high as 2% to 5 % children born in the US, and prevalence is [...] Read more.
Fetal alcohol spectrum disorder (FASD), caused by prenatal alcohol exposure, can result in craniofacial dysmorphism, cognitive impairment, sensory and motor disabilities among other defects. FASD incidences are as high as 2% to 5 % children born in the US, and prevalence is higher in low socioeconomic populations. Despite various mechanisms being proposed to explain the etiology of FASD, the molecular targets of ethanol toxicity during development are unknown. Proposed mechanisms include cell death, cell signaling defects and gene expression changes. More recently, the involvement of several other molecular pathways was explored, including non-coding RNA, epigenetic changes and specific vitamin deficiencies. These various pathways may interact, producing a wide spectrum of consequences. Detailed understanding of these various pathways and their interactions will facilitate the therapeutic target identification, leading to new clinical intervention, which may reduce the incidence and severity of these highly prevalent preventable birth defects. This review discusses manifestations of alcohol exposure on the developing central nervous system, including the neural crest cells and sensory neural placodes, focusing on molecular neurodevelopmental pathways as possible therapeutic targets for prevention or protection. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Open AccessReview Long-Lasting Neural Circuit Dysfunction Following Developmental Ethanol Exposure
Brain Sci. 2013, 3(2), 704-727; doi:10.3390/brainsci3020704
Received: 27 February 2013 / Revised: 10 April 2013 / Accepted: 23 April 2013 / Published: 29 April 2013
Cited by 10 | PDF Full-text (554 KB) | HTML Full-text | XML Full-text
Abstract
Fetal Alcohol Spectrum Disorder (FASD) is a general diagnosis for those exhibiting long-lasting neurobehavioral and cognitive deficiencies as a result of fetal alcohol exposure. It is among the most common causes of mental deficits today. Those impacted are left to rely on [...] Read more.
Fetal Alcohol Spectrum Disorder (FASD) is a general diagnosis for those exhibiting long-lasting neurobehavioral and cognitive deficiencies as a result of fetal alcohol exposure. It is among the most common causes of mental deficits today. Those impacted are left to rely on advances in our understanding of the nature of early alcohol-induced disorders toward human therapies. Research findings over the last decade have developed a model where ethanol-induced neurodegeneration impacts early neural circuit development, thereby perpetuating subsequent integration and plasticity in vulnerable brain regions. Here we review our current knowledge of FASD neuropathology based on discoveries of long-lasting neurophysiological effects of acute developmental ethanol exposure in animal models. We discuss the important balance between synaptic excitation and inhibition in normal neural network function, and relate the significance of that balance to human FASD as well as related disease states. Finally, we postulate that excitation/inhibition imbalance caused by early ethanol-induced neurodegeneration results in perturbed local and regional network signaling and therefore neurobehavioral pathology. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)
Figures

Open AccessReview Involvement of Sphingolipids in Ethanol Neurotoxicity in the Developing Brain
Brain Sci. 2013, 3(2), 670-703; doi:10.3390/brainsci3020670
Received: 21 February 2013 / Revised: 30 March 2013 / Accepted: 12 April 2013 / Published: 26 April 2013
Cited by 2 | PDF Full-text (382 KB) | HTML Full-text | XML Full-text
Abstract
Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of fetal alcohol spectrum disorders (FASD). In rodent models, ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first [...] Read more.
Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of fetal alcohol spectrum disorders (FASD). In rodent models, ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first two postnatal weeks, equivalent to the third trimester in human fetuses. The ethanol-induced apoptosis is mitochondria-dependent, involving Bax and caspase-3 activation. Such apoptotic pathways are often mediated by sphingolipids, a class of bioactive lipids ubiquitously present in eukaryotic cellular membranes. While the central role of lipids in ethanol liver toxicity is well recognized, the involvement of sphingolipids in ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis. Nevertheless, recent studies indicate that ethanol-induced neuronal apoptosis in animal models of FASD is mediated or regulated by cellular sphingolipids, including via the pro-apoptotic action of ceramide and through the neuroprotective action of GM1 ganglioside. Such sphingolipid involvement in ethanol neurotoxicity in the developing brain may provide unique targets for therapeutic applications against FASD. Here we summarize findings describing the involvement of sphingolipids in ethanol-induced apoptosis and discuss the possibility that the combined action of various sphingolipids in mitochondria may control neuronal cell fate. Full article
(This article belongs to the Special Issue Ethanol Neurotoxicity)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of paper: Article
Title: Ethanol Modulates Spontaneous Calcium Waves in Axonal Growth Cones in Vitro
Authors: Tara A. Lindsley and Jessica Donnelly
Affiliation: Center for Neuropharmacology & Neuroscience, Albany Medical College (MC-136), 47 New Scotland Ave., Albany, NY 12208, USA; E-Mail:lindslt@mail.amc.edu
Abstract: In developing neurons the frequency of spontaneous, transient calcium elevations localized to the growth cone is inversely related to the rate of axon elongation and increases several fold when axons pause. Here we report that these growth cone calcium waves are modulated by conditions of ethanol exposure that alter axonal growth dynamics. Using time-series Fluo-3 confocal imaging we found that acute treatment of fetal rat hippocampal neurons with 43 or 87 mM ethanol at an early stage of development in culture dramatically decreased percent of axonal growth cones showing at least one Ca2+ transient during 10 min of recording, from 18% in controls to 5% in cultures exposed to ethanol. Chronic exposure to 43 mM ethanol also reduced the frequency of Ca2+ transients in growth cones to 8%, but 87 mM ethanol increased their frequency to 40%. Neither chronic nor acute ethanol affected the peak amplitude, time to peak or total duration of transients. In some experiments, we determined the correlation between rate of axon elongation (or retraction) and frequency of transients. As expected, increases in transient frequency were correlated with pausing in control and ethanol treated growth cones, except in cultures exposed chronically to 87mM ethanol. Thus, the relationship between growth cone Ca2+ wave frequency and axon growth dynamics is disrupted by ethanol.

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