Ethanol-induced decrease of developmental PKC isoform expression in the embryonic chick brain

McIntyre, Timothy A.; Souder, Matthew G.; Hartl, Michael; Shibley, Ivan A.

doi:10.1016/s0165-3806(99)00122-4

Cited by 10 publications

(7 citation statements)

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“…PKC expression and/or activity have been found to be reduced in FAS models (21,22). Accordingly, we found that the expression of membrane PKC␥ [the main isoform expressed in PCs and not in other cerebellar neurons as demonstrated by immunohistochemistry (21) and in situ hybridization (23)] is significantly reduced in the cerebellum of FAS mice as demonstrated by Western blotting. We have then tested the effect of a PKC activator and a PKC inhibitor on the maximal amplitude of voltage-dependent calcium current.…”

Section: Discussionmentioning

confidence: 53%

“…Finally, PKC directly increases the activity of Ca v 1.2 and Ca v 2 channels and reverses G protein inhibition of these channels (41). PKC expression and/or activity have been found to be reduced in FAS models (21,22). Accordingly, we found that the expression of membrane PKC␥ [the main isoform expressed in PCs and not in other cerebellar neurons as demonstrated by immunohistochemistry (21) and in situ hybridization (23)] is significantly reduced in the cerebellum of FAS mice as demonstrated by Western blotting.…”

Section: Discussionmentioning

confidence: 99%

“…Because the activation of VGCC relies on channels phosphorylation by PKC and because a decreased expression of PKC enzyme was observed in previous FAS models (21,22), we studied the expression of the membrane-bound ␥-isoform (PKC␥) that is highly expressed in PCs (23) by using Western blot analysis. We found that the normalized level of PKC␥ was significantly reduced in FAS mice (n ϭ 6) compared with control mice (n ϭ 8, P Ͻ 0.05) (Fig.…”

Section: Reduced Pkc␥ Expression Causes Reduced Voltage-gated Calciummentioning

confidence: 99%

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Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome

Servais

Hourez²,

Bearzatto³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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In cerebellum and other brain regions, neuronal cell death because of ethanol consumption by the mother is thought to be the leading cause of neurological deficits in the offspring. However, little is known about how surviving cells function. We studied cerebellar Purkinje cells in vivo and in vitro to determine whether function of these cells was altered after prenatal ethanol exposure. We observed that Purkinje cells that were prenatally exposed to ethanol presented decreased voltage-gated calcium currents because of a decreased expression of the ␥-isoform of protein kinase C. Longterm depression at the parallel fiber-Purkinje cell synapse in the cerebellum was converted into long-term potentiation. This likely explains the dramatic increase in Purkinje cell firing and the rapid oscillations of local field potential observed in alert fetal alcohol syndrome mice. Our data strongly suggest that reversal of longterm synaptic plasticity and increased firing rates of Purkinje cells in vivo are major contributors to the ataxia and motor learning deficits observed in fetal alcohol syndrome. Our results show that calcium-related neuronal dysfunction is central to the pathogenesis of the neurological manifestations of fetal alcohol syndrome and suggest new methods for treatment of this disorder.calcium ͉ cerebellum ͉ protein kinase ͉ long-term depression ͉ motor learning F etal alcohol syndrome (FAS) is the leading cause of intellectual disability in the Western world with a prevalence of 1 to 1.5 cases per 1,000 live births (1) and a lifetime cost of care of approximately $1.4 million per case. This cost is mainly because of ethanol toxicity in the developing central nervous system, causing intellectual disability, deficits in learning, and fine-motor dysfunction (2).The cerebellum is one of the main targets of in utero ethanol toxicity (3). Within the cerebellum, Purkinje cells (PCs) are highly sensitive to ethanol. PCs constitute the sole output of the cerebellar cortex and thus have a central functional role in integration. All animal models of FAS display a reduction in the number of PCs by Ϸ20% (4), and various authors have proposed that neuronal loss is the only cause of cerebellar deficits in FAS. One study conducted on adult anesthetized rats with FAS led to the conclusion that PCs that survive ethanol administration function normally (5). Thomas et al. (6) found a correlation between total PCs number and motor performance. These experimental data led to the assumption that surviving PCs function normally and that motor coordination impairment in FAS results only from a quantitative defect of PCs. This is crucially important from a therapeutic point of view because very few options exist to replace dead neurons. Many studies have therefore focused on different ways to decrease PC loss in FAS (7,8). However, different models of ataxia that result from PC death per se (pcd mice, SV4 mice, T147 transgenic mice) have demonstrated that considerable neuropathology can occur without the manifestation of a neurologic...

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Reduced Pkc␥ Expression Causes Reduced Voltage-gated Calciummentioning

confidence: 99%

See 1 more Smart Citation

Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome

Servais

Hourez²,

Bearzatto³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…In the CA1 region of rat hippocampus, PKC γ is localized in the soma including the nucleus and in dendrites including dendritic spines, axon and synaptic terminals (Kose et al ., 1990). In embryonic chick brain, ethanol caused a decreased expression of PKC γ on days 7 to 10 (McIntyre et al ., 1999), suggesting that this PKC isozyme is regulated by ethanol. PKC γ has been implicated in synaptic plasticity (Saito & Shirai, 2002).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase Cγ mediates ethanol withdrawal hyper‐responsiveness of NMDA receptor currents in spinal cord motor neurons

Mochly‐Rosen

Kendig

2005

British J Pharmacology

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1 The present studies were designed to test the hypothesis that neuronal-specific protein kinase Cg (PKCg) plays a critical role in acute ethanol withdrawal hyper-responsiveness in spinal cord. 2 Patch-clamp studies were carried out in motor neurons in neonatal rat spinal cord slices. Postsynaptic currents were evoked by brief pulses of 2 mM N-methyl-D-aspartic acid (NMDA) in the presence of bicuculline methiodide 10 mM; strychnine 5 mM and tetrodotoxin 0.5 mM. 3 Both ethanol depression and withdrawal hyper-responsiveness of NMDA-evoked currents are dependent on increases in intracellular Ca 2 þ . Blocking intracellular increase in Ca 2 þ by 30 mM 1,2-bis(2-aminophenoxy)-ethane-N,N,N 0 ,N 0 -tetraacetic acid (BAPTA) not only decreased the ethanolinduced depression of NMDA-evoked currents (3375% in control vs 2073% in BAPTA, Po0.05) but also eliminated acute ethanol withdrawal hyper-responsiveness. 4 Immunohistochemistry studies revealed that neonatal spinal cord motor neurons contain an abundance of nuclear PKCg. 5 Exposure to ethanol (100 mM) induced PKCg translocation from the nucleus to cytoplasm in motor neurons. Pretreatment with the g-isozyme-specific peptide PKC inhibitor, gV5-3, blocked ethanol-induced translocation and also blocked withdrawal hyper-responsiveness. 6 The results show that PKCg mediates ethanol withdrawal hyper-responsiveness in spinal motor neurons; the results may be relevant to some symptoms of ethanol withdrawal in vivo.

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“…A series of studies by Pennington, Shibley, and colleagues (1983 – 2001) supported that ethanol (~60 mg/egg; BACs 5–90 mg/dl on embryonic day 7; Pennington 1988) mediates this growth suppression, because co-administration of the ADH inhibitor 4-methyl-pyrazole, which would prevent oxidation of ethanol to acetaldehyde, did not normalize growth (Pennington 1988, 1990). Deficits in growth and proliferation in these embryos were associated with reductions in cAMP and protein kinase A (Pennington 1990; Boyd et al 1984), and a parallel decline in PKC activity (Shibley et al 1997) and selective reductions in PKC-α, -γ, and -ε (McIntyre et al 1999). Addition of an anabolic agent in the form of exogenous insulin could not overcome this growth impairment (Pennington et al 1995), and, unexpectedly, cells from alcohol-treated embryos had dramatically increased glucose uptake in response to insulin (Shibley et al 1997; Pennington et al 1995; Carver et al 1999), elevated PI3 kinase activity (Shibley et al 1997), and increased brain glucose content (Eckstein et al 1997), perhaps indicative of alcohol-driven metabolic stress.…”

Section: Mechanistic Insights From Avian Models Of Fasdmentioning

confidence: 99%

The avian embryo as a model for fetal alcohol spectrum disorder

Flentke

Smith

2018

Biochem. Cell Biol.

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Prenatal alcohol exposure (PAE) remains a leading preventable cause of structural birth defects and permanent neurodevelopmental disability. The chick (Gallus gallus domesticus) is a powerful embryological research model and was possibly the first (Fere, 1895) in which alcohol’s teratogenicity was demonstrated. Pharmacologically relevant alcohol exposures in the range of 20–70 mM (20–80 mg/egg) disrupt chick embryo growth, morphogenesis, and behavior, and the resulting phenotypes strongly parallel those of mammalian models. The avian embryo’s direct accessibility has enabled novel insights into alcohol’s teratogenic mechanisms. These include the contribution of IGF1 signaling to growth suppression, the altered flow dynamics that reshape valvuloseptal morphogenesis and mediate its cardiac teratogenicity, and the suppression of Wnt and Shh signals to disrupt neural crest migration, expansion, and survival and underlie its characteristic craniofacial deficits. The genetic diversity within commercial avian strains enabled identification of unique loci, such as ribosome biogenesis, that modify vulnerability to alcohol. This venerable research model is equally relevant for the future, as the application of technological advances including CRISPR, optogenetics, and biophotonics to the embryo’s ready accessibility creates a unique model in which investigators can manipulate and monitor the embryo in real-time to investigate alcohol’s actions upon cell fate.

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Ethanol-induced decrease of developmental PKC isoform expression in the embryonic chick brain

Cited by 10 publications

References 50 publications

Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome

Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome

Protein kinase Cγ mediates ethanol withdrawal hyper‐responsiveness of NMDA receptor currents in spinal cord motor neurons

The avian embryo as a model for fetal alcohol spectrum disorder

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