Increased Ethanol Resistance and Consumption in Eps8 Knockout Mice Correlates with Altered Actin Dynamics

Offenhäuser, Nina; Castelletti, Daniela; Mapelli, Lisa; Soppo, Blanche Ekalle; Regondi, Maria Cristina; Rossi, Paola; D’Angelo, Egidio; Frassoni, Carolina; Amadeo, Alida; Tocchetti, Arianna; Pozzi, Benedetta; Disanza, Andrea; Guarnieri, Douglas J.; Betsholtz, Christer; Scita, Giorgio; Heberlein, Ulrike; Fiore, Pier Paolo Di

doi:10.1016/j.cell.2006.09.011

Cited by 117 publications

(129 citation statements)

References 64 publications

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“…Alternatively, there might be an increase in the synaptic content of NMDA receptors or in the functional properties of NMDA receptors (i.e., through receptor phosphorylation). Of note, genetic ablation of Eps8, a direct binding partner of IRSp53, enhances NMDA receptor responses through increases in the amplitude and decay kinetics of NMDA currents (Offenhäuser et al, 2006). It is possible that IRSp53 and Eps8 may act in concert to regulate NMDA receptor responses, although the expression levels of Eps8 were not changed in IRSp53 Ϫ/Ϫ mice.…”

Section: Regulation Of Nmda Receptor-mediated Transmission By Irsp53mentioning

confidence: 90%

Enhanced NMDA Receptor-Mediated Synaptic Transmission, Enhanced Long-Term Potentiation, and Impaired Learning and Memory in Mice Lacking IRSp53

Kim¹,

Choi²,

Yang³

et al. 2009

J. Neurosci.

130

135

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Section: Regulation Of Nmda Receptor-mediated Transmission By Irsp53mentioning

confidence: 90%

Enhanced NMDA Receptor-Mediated Synaptic Transmission, Enhanced Long-Term Potentiation, and Impaired Learning and Memory in Mice Lacking IRSp53

Kim¹,

Choi²,

Yang³

et al. 2009

J. Neurosci.

130

135

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“…For instance, the involvement of other cerebellar neurons, such as molecular layer interneurons, Golgi, or granule cells, and of their respective synaptic plasticity, was not studied here. Other cerebellar neurons, for instance granule cells, are known to be sensitive to ethanol (34). In addition, we did not rule out that increased simple spike firing in FAS could partially result from hyperexcitation of extracerebellar areas that project on the cerebellum.…”

Section: Discussionmentioning

confidence: 99%

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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“…These possibilities for modulation of lipid rafts and associated cellular function are likely to occur beyond TLRs and immune cells. Recent reports (78,79) indicate that recruitment of different receptor components to rafts and actin polymerization were inhibited in rat adipocytes and mouse neurons by administration of EtOH, suggesting that this mechanism may contribute to the effects of EtOH on signaling through a number of receptor types in which lipid rafts play a role. In conclusion, we propose that the influence of EtOH on lipid raft-mediated dynamics and signaling of TLRs, and possibly other receptors, constitutes a previously unrecognized mechanism that may contribute, along with other mechanisms, to alcoholinduced modulation of the immune cell functions.…”

Section: Conclusion and Implications For Effects Of Etoh In Other Phmentioning

confidence: 99%

TLR4, Ethanol, and Lipid Rafts: A New Mechanism of Ethanol Action with Implications for other Receptor-Mediated Effects

Szabó

Dolganiuc

Dai

et al. 2007

The Journal of Immunology

125

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Ethanol (EtOH) is the most widely abused substance in the United States, and it contributes to well-documented harmful (at high dosages) and beneficial (at low dosages) changes in inflammatory and immune responses. Lipid rafts have been implicated in the regulation and activation of several important receptor complexes in the immune system, including the TLR4 complex. Many questions remain about the precise mechanisms by which rafts regulate the assembly of these receptor complexes. Results summarized in this review indicate that EtOH acts by altering the LPS-induced redistribution of components of the TLR4 complex within the lipid raft and that this is related to changes in actin cytoskeleton rearrangement, receptor clustering, and subsequent signaling. EtOH provides an example of an immunomodulatory drug that acts at least in part by modifying lipid rafts, and it could represent a model to probe the relationships between rafts, receptor complexes, and signaling.

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Increased Ethanol Resistance and Consumption in Eps8 Knockout Mice Correlates with Altered Actin Dynamics

Cited by 117 publications

References 64 publications

Enhanced NMDA Receptor-Mediated Synaptic Transmission, Enhanced Long-Term Potentiation, and Impaired Learning and Memory in Mice Lacking IRSp53

Enhanced NMDA Receptor-Mediated Synaptic Transmission, Enhanced Long-Term Potentiation, and Impaired Learning and Memory in Mice Lacking IRSp53

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

TLR4, Ethanol, and Lipid Rafts: A New Mechanism of Ethanol Action with Implications for other Receptor-Mediated Effects

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