Astrocytes play a critical role in mediating the effect of acute ethanol on central amygdala glutamatergic transmission

Severe stress can trigger complex behavioural changes such as high anxiety (1). Inhibitory GABA-ergic interneurons in the lateral division of the central amygdala (CEl) control anxiety through feedforward inhibition of their target cells in the medial division (CEm) (2, 3). In particular, PKCδ-positive (PKCδ+) interneurons in CEl are critical elements of the neuronal circuitry of fear and anxiety (3-5), but the molecular mechanisms they employ are poorly understood. Here, we show that, during stress, GABA-ergic synapses of amygdala PKCδ+ interneurons are regulated by a serine protease plasmin. On stress, plasmin cleaves the extracellular portion of the tyrosine kinase receptor EphA4 triggering its dissociation from gephyrin, a postsynaptic GABA-receptor anchoring protein. Dynamic EphA4/gephyrin interaction leads to modification of dendritic spine morphology and synaptic GABA-receptor expression profile. Consistent with the critical role for the plasmin/EphA4/gephyrin signalling axis in anxiogenesis, viral delivery of plasmin-resistant (prEphA4) form of EphA4 into the central amygdala prevents the development of stress-induced anxiety in mice, while the delivery of plasmin-truncated EphA4 (tEphA4) dramatically enhances this effect. Thus, our studies identify a novel, critical molecular cascade regulating GABA-ergic signalling in the central amygdala synapses that allows bidirectional switching of animal behaviour from high to low anxiety states.

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Acute and Chronic Ethanol Alter Glutamatergic Transmission in Rat Central Amygdala: an In Vitro and In Vivo Analysis

Journal of Neuroscience ◽

10.1523/jneurosci.5077-03.2004 ◽

2004 ◽

Vol 24 (7) ◽

pp. 1594-1603 ◽

Cited By ~ 187

Author(s):

M. Roberto

Keyword(s):

Chronic Ethanol ◽

Glutamatergic Transmission ◽

Central Amygdala ◽

In Vivo Analysis

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Ethanol Produces Corticotropin-Releasing Factor Receptor-Dependent Enhancement of Spontaneous Glutamatergic Transmission in the Mouse Central Amygdala

Alcoholism Clinical and Experimental Research ◽

10.1111/acer.12881 ◽

2015 ◽

Vol 39 (11) ◽

pp. 2154-2162 ◽

Cited By ~ 8

Author(s):

Yuval Silberman ◽

Tracy L. Fetterly ◽

Elias K. Awad ◽

Elana J. Milano ◽

Ted B. Usdin ◽

...

Keyword(s):

Corticotropin Releasing Factor ◽

Glutamatergic Transmission ◽

Central Amygdala

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Presynaptic CRF1 Receptors Mediate the Ethanol Enhancement of GABAergic Transmission in the Mouse Central Amygdala

The Scientific World JOURNAL ◽

10.1100/tsw.2009.1 ◽

2009 ◽

Vol 9 ◽

pp. 68-85 ◽

Cited By ~ 39

Author(s):

Zhiguo Nie ◽

Eric P. Zorrilla ◽

Samuel G. Madamba ◽

Kenner C. Rice ◽

Marissa Roberto ◽

...

Keyword(s):

Synaptic Transmission ◽

Stress Responses ◽

Critical Role ◽

Strong Relationship ◽

Gaba Release ◽

Dependent Manner ◽

Central Amygdala ◽

Concentration Dependent Manner ◽

Excessive Alcohol Consumption ◽

Gabaergic Synaptic Transmission

Corticotropin-releasing factor (CRF) is a 41-amino-acid neuropeptide involved in stress responses initiated from several brain areas, including the amygdala formation. Research shows a strong relationship between stress, brain CRF, and excessive alcohol consumption. Behavioral studies suggest that the central amygdala (CeA) is significantly involved in alcohol reward and dependence. We recently reported that the ethanol augmentation of GABAergic synaptic transmission in rat CeA involves CRF1 receptors, because both CRF and ethanol significantly enhanced the amplitude of evoked GABAergic inhibitory postsynaptic currents (IPSCs) in CeA neurons from wild-type (WT) and CRF2 knockout (KO) mice, but not in neurons of CRF1KO mice. The present study extends these findings using selective CRF receptor ligands, gene KO models, and miniature IPSC (mIPSC) analysis to assess further a presynaptic role for the CRF receptors in mediating ethanol effects in the CeA. In whole-cell patch recordings of pharmacologically isolated GABAAergic IPSCs from slices of mouse CeA, both CRF and ethanol augmented evoked IPSCs in a concentration-dependent manner, with low EC50s. A CRF1(but not CRF2) KO construct and the CRF1-selective nonpeptide antagonist NIH-3 (LWH-63) blocked the augmenting effect of both CRF and ethanol on evoked IPSCs. Furthermore, the new selective CRF1agonist stressin1, but not the CRF2agonist urocortin 3, also increased evoked IPSC amplitudes. Both CRF and ethanol decreased paired-pulse facilitation (PPF) of evoked IPSCs and significantly enhanced the frequency, but not the amplitude, of spontaneous miniature GABAergic mIPSCs in CeA neurons of WT mice, suggesting a presynaptic site of action. The PPF effect of ethanol was abolished in CeA neurons of CRF1KO mice. The CRF1antagonist NIH-3 blocked the CRF- and ethanol-induced enhancement of mIPSC frequency in CeA neurons. These data indicate that presynaptic CRF1receptors play a critical role in permitting or mediating ethanol enhancement of GABAergic synaptic transmission in CeA, via increased vesicular GABA release, and thus may be a rational target for the treatment of alcohol abuse and alcoholism.

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Dexamethasone Effect on Embryonic Chick Respiratory Epithelium

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053905 ◽

1982 ◽

Vol 40 ◽

pp. 248-249

Author(s):

M.R. Richter ◽

R.V. Blystone

Keyword(s):

Lung Development ◽

Critical Role ◽

Respiratory Epithelium ◽

Chick Embryos ◽

Embryonic Chick ◽

White Leghorn ◽

Lung Maturation ◽

Synthetic Analogs ◽

Lung Physiology ◽

Avian Lung

Dexamethasone and other synthetic analogs of corticosteroids have been employed clinically as enhancers of lung development. The mechanism(s) by which this steroid induction of later lung maturation operates is not clear. This study reports the effect on lung epithelia of dexamethasone administered at different intervals during development. White Leghorn chick embryos were used so as to remove possible maternal and placental influences on the exogenously applied steroid. Avian lung architecture does vary from mammals; however, respiratory surfactant produced by the lung epithelia serves an equally critical role in avian lung physiology.

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An atomic resolution study of a carbide phase in platinum

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100120503 ◽

1992 ◽

Vol 50 (1) ◽

pp. 20-21

Author(s):

M.J. Witcomb ◽

M.A. O'Keefe ◽

CJ. Echer ◽

C. Nelson ◽

J.H. Turner ◽

...

Keyword(s):

Solid Solution ◽

Carbon Atom ◽

Carbide Phase ◽

Structural Changes ◽

Critical Role ◽

Alloy System ◽

Atomic Resolution ◽

Excess Carbon ◽

Interstitial Carbon ◽

Resolution Study

Under normal circumstances, Pt dissolves only a very small amount of interstitial carbon in solid solution. Even so, an appropriate quench/age treatment leads to the formation of stable Pt2C {100} plate precipitates. Excess (quenched-in) vacancies play a critical role in the process by accommodating the volume and structural changes that accompany the transformation. This alloy system exhibits other interesting properties. Due to a large vacancy/carbon atom binding energy, Pt can absorb excess carbon at high temperatures in a carburizing atmosphere. In regions rich in carbon and vacancies, another carbide phase, Pt7C which undergoes an order-disorder reaction was formed. The present study of Pt carburized at 1160°C and aged at 515°C shows that other carbides in the PtxC series can be produced.

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Quantitative Model-Based Image Analysis of NuMa Distribution Links Nuclear Organization with Cell Phenotype

Microscopy and Microanalysis ◽

10.1017/s1431927600028968 ◽

2001 ◽

Vol 7 (S2) ◽

pp. 578-579

Author(s):

David W. Knowles ◽

Sophie A. Lelièvre ◽

Carlos Ortiz de Solόrzano ◽

Stephen J. Lockett ◽

Mina J. Bissell ◽

...

Keyword(s):

Image Analysis ◽

Mammary Epithelial Cells ◽

Nuclear Organization ◽

Critical Role ◽

Quantitative Model ◽

Mammary Epithelial ◽

Cell Phenotype ◽

Proliferating Cells ◽

Mitotic Apparatus ◽

Model Based

The extracellular matrix (ECM) plays a critical role in directing cell behaviour and morphogenesis by regulating gene expression and nuclear organization. Using non-malignant (S1) human mammary epithelial cells (HMECs), it was previously shown that ECM-induced morphogenesis is accompanied by the redistribution of nuclear mitotic apparatus (NuMA) protein from a diffuse pattern in proliferating cells, to a multi-focal pattern as HMECs growth arrested and completed morphogenesis . A process taking 10 to 14 days.To further investigate the link between NuMA distribution and the growth stage of HMECs, we have investigated the distribution of NuMA in non-malignant S1 cells and their malignant, T4, counter-part using a novel model-based image analysis technique. This technique, based on a multi-scale Gaussian blur analysis (Figure 1), quantifies the size of punctate features in an image. Cells were cultured in the presence and absence of a reconstituted basement membrane (rBM) and imaged in 3D using confocal microscopy, for fluorescently labeled monoclonal antibodies to NuMA (fαNuMA) and fluorescently labeled total DNA.

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