Neurological Findings in the Fetal Alcohol Syndrome*

Marcus, Joseph C.

doi:10.1055/s-2008-1052471

Cited by 93 publications

(32 citation statements)

References 11 publications

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“…The ability of prenatal ethanol exposure to induce brain damage that can result in severe mental retardation linked to fetal alcohol syndrome, or associated attention disorders and hyperactivity, has been well documented (56,57). The cerebellar region of the developing central nervous system is particularly sensitive to ethanol-induced cell injury, with decreases in cerebellar size, the number of granule and Purkinje neurons, and delayed neuronal maturation and synapse formation, all consequences of ethanol exposure (58,59).…”

Section: Discussionmentioning

confidence: 99%

N-Methyl-d-aspartate Inhibits Apoptosis through Activation of Phosphatidylinositol 3-Kinase in Cerebellar Granule Neurons

Zhang

Rubin

Rooney

1998

Journal of Biological Chemistry

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Primary cultured rat cerebellar granule neurons underwent apoptosis when switched from medium containing 25 mM K ؉ to one containing 5 mM K ؉ . N-methyl-D-aspartate (NMDA) protected granule neurons from apoptosis in medium containing 5 mM K ؉ . Inhibition of apoptosis by NMDA was blocked by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002, but it was unaffected by the mitogen-activated protein kinase kinase inhibitor PD 98059. The antiapoptotic action of NMDA was associated with an increase in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), an increase in the binding of the regulatory subunit of PI 3-kinase to IRS-1, and a stimulation of PI 3-kinase activity. In the absence of extracellular Ca 2؉ , NMDA was unable to prevent apoptosis or to phosphorylate IRS-1 and activate PI 3-kinase. Significant inhibition of NMDA-mediated neuronal survival by ethanol (10 -15%) was observed at 1 mM, and inhibition was half-maximal at 45-50 mM. Inhibition of neuronal survival by ethanol corresponded with a marked reduction in the capacity of NMDA to increase the concentration of intracellular Ca 2؉ , phosphorylate IRS-1, and activate PI 3-kinase. These data demonstrate that the neurotrophic action of NMDA and its inhibition by ethanol are mediated by alterations in the activity of a PI 3-kinase-dependent antiapoptotic signaling pathway.Glutamate functions as the major excitatory neurotransmitter in the mammalian central nervous system by activating ionotropic and metabotropic glutamate receptors (1, 2). The NMDA 1 receptor is an important subtype of ionotropic glutamate receptors that functions as a ligand-gated ion channel and initiates cation influx upon activation by glutamate or NMDA (3, 4). Activated NMDA receptors are about 10 times more permeable to Ca 2ϩ than to Na ϩ and contain regulatory sites for Mg 2ϩ , Zn 2ϩ , glycine, polyamines, and phencyclidine (3, 4). An increase in [Ca 2ϩ ] i is central to many of the properties of NMDA receptor activation in the central nervous system, including its role in development, neuroplasticity, and neurotoxicity (4, 5).NMDA receptors can produce neurotrophic and/or neurotoxic effects in brain, depending on the stage of development and the degree of receptor activation. During restricted developmental periods, NMDA receptor activation has been shown to be important for maintaining neuronal survival, synaptogenesis, synaptic plasticity, learning, and memory (5, 6). However, excessive NMDA receptor activation can result in neuronal damage and cell death (7). Recent studies have shown that glutamate-induced cell death in cerebellar granule neurons is composed of sequential necrosis and apoptosis (8). After exposure to glutamate, a subpopulation of granule neurons undergoes rapid necrotic cell killing that is associated with a loss of mitochondrial function. Neurons surviving the early necrotic phase recover their mitochondrial potential and energy levels and sustain delayed apoptotic cell death. Glutamate-induced apoptosis has been shown to invo...

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Section: Discussionmentioning

confidence: 99%

N-Methyl-d-aspartate Inhibits Apoptosis through Activation of Phosphatidylinositol 3-Kinase in Cerebellar Granule Neurons

Zhang

Rubin

Rooney

1998

Journal of Biological Chemistry

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“…Microcephaly is present in nearly all cases, and this reflection of disturbed brain growth is accompanied by delayed neurologic development in approximately 90% of the cases [90,91,96] . Particular defects of speech and language development are also evident [92] . In addition to serious cognitive deficits, a far-reaching and pervasive state of disability is induced by behavioral disturbances, impaired communication skills and maladaptive social function, manifested by lack of reciprocal friendships, impulsive behavior, anxiety and dysphoria.…”

Section: Effects Of Alcohol On Brain Developmentmentioning

confidence: 99%

“…Prolonged exposure to alcohol during gestation and lactation correlates with a pattern of abnormal development in newborns [90][91][92] . Jones and Smith [93] called this developmental disturbance 'fetal alcohol syndrome' (FAS).…”

Section: Effects Of Alcohol On Brain Developmentmentioning

confidence: 99%

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Cerebellar Granule Cell Migration and the Effects of Alcohol

et al. 2007

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In the developing brain the majority of neurons migrate from their birthplace to their final destination. This active movement is essential for the formation of cortical layers and nuclei. The impairment of migration does not affect the viability of neurons but often results in abnormal differentiation. The proper migration of neurons requires the orchestrated activities of multiple cellular and molecular events, such as pathway selection, the activation of specific receptors and channels, and the assembly and disassembly of cytoskeletal components. The migration of neurons is very vulnerable to exposure to environmental toxins, such as alcohol. In this article, we will focus on recent developments in the migration of cerebellar granule cells. First, we will describe when, where and how granule cells migrate through different cortical layers to reach their final destination. Second, we will present how internal programs control the sequential changes in granule cell migration. Third, we will review the roles of external guidance cues and transmembrane signals in granule cell migration. Finally, we will reveal mechanisms by which alcohol exposure impairs granule cell migration.

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“…Jones and Smith (1973) called this developmental disturbance "fetal alcohol syndrome" (FAS). The disturbance of the CNS is the most serious feature of FAS (Marcus, 1987;Riley and McGee, 2005;Welch-Carre, 2005). For example, microencephaly is common among patients with FAS (Wisniewski et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

Reversal of Neuronal Migration in a Mouse Model of Fetal Alcohol Syndrome by Controlling Second-Messenger Signalings

Kumada¹,

Lakshmana²,

Komuro³

2006

J. Neurosci.

131

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The brains of fetal alcohol syndrome patients exhibit impaired neuronal migration, but little is known about the mechanisms underlying this abnormality. Here we show that Ca 2ϩ signaling and cyclic nucleotide signaling are the central targets of alcohol action in neuronal cell migration. Acute administration of ethanol reduced the frequency of transient Ca 2ϩ elevations in migrating neurons and cGMP levels and increased cAMP levels. Experimental manipulations of these second-messenger pathways, through stimulating Ca 2ϩ and cGMP signaling or inhibiting cAMP signaling, completely reversed the action of ethanol on neuronal migration in vitro as well as in vivo. Each second messenger has multiple but distinct downstream targets, including Ca 2ϩ /calmodulin-dependent protein kinase II, calcineurin, protein phosphatase 1, Rho GTPase, mitogen-activated protein kinase, and phosphoinositide 3-kinase. These results demonstrate that the aberrant migration of immature neurons in the fetal brain caused by maternal alcohol consumption may be corrected by controlling the activity of these second-messenger pathways.

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Neurological Findings in the Fetal Alcohol Syndrome*

Cited by 93 publications

References 11 publications

N-Methyl-d-aspartate Inhibits Apoptosis through Activation of Phosphatidylinositol 3-Kinase in Cerebellar Granule Neurons

N-Methyl-d-aspartate Inhibits Apoptosis through Activation of Phosphatidylinositol 3-Kinase in Cerebellar Granule Neurons

Cerebellar Granule Cell Migration and the Effects of Alcohol

Reversal of Neuronal Migration in a Mouse Model of Fetal Alcohol Syndrome by Controlling Second-Messenger Signalings

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