scholarly journals GluA1 Phosphorylation Alters Evoked Firing PatternIn Vivo

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Balázs Barkóczi ◽  
Gábor Juhász ◽  
Robert G. Averkin ◽  
Imre Vörös ◽  
Petra Vertes ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Spike Trains ◽  
Temporal Coding ◽  
Relative Contribution ◽  
Ampa Receptor Subunit ◽  
Ampa And Nmda Receptors ◽  
Characteristic Features ◽  
Evoked Activity

AMPA and NMDA receptors convey fast synaptic transmission in the CNS. Their relative contribution to synaptic output and phosphorylation state regulate synaptic plasticity. The AMPA receptor subunit GluA1 is central in synaptic plasticity. Phosphorylation of GluA1 regulates channel properties and trafficking. The firing rate averaged over several hundred ms is used to monitor cellular input. However, plasticity requires the timing of spiking within a few ms; therefore, it is important to understand how phosphorylation governs these events. Here, we investigate whether the GluA1 phosphorylation (p-GluA1) alters the spiking patterns of CA1 cellsin vivo. The antidepressant Tianeptine was used for inducing p-GluA1, which resulted in enhanced AMPA-evoked spiking. By comparing the spiking patterns of AMPA-evoked activity with matched firing rates, we show that the spike-trains after Tianeptine application show characteristic features, distinguishing from spike-trains triggered by strong AMPA stimulation. The interspike-interval distributions are different between the two groups, suggesting that neuronal output may differ when new inputs are activated compared to increasing the gain of previously activated receptors. Furthermore, we also show that NMDA evokes spiking with different patterns to AMPA spike-trains. These results support the role of the modulation of NMDAR/AMPAR ratio and p-GluA1 in plasticity and temporal coding.

Toward heterogeneity in feedforward network with synaptic delays based on FitzHugh–Nagumo model

2018 ◽  
Vol 32 (01) ◽  
pp. 1750274 ◽  
Author(s):  
Ying-Mei Qin ◽  
Cong Men ◽  
Jia Zhao ◽  
Chun-Xiao Han ◽  
Yan-Qiu Che
Keyword(s):  
Neuronal Excitability ◽  
Temporal Coding ◽  
Feedforward Network ◽  
Firing Patterns ◽  
In Vivo Experiments ◽  
Connection Probability ◽  
Rate Coding

We focus on the role of heterogeneity on the propagation of firing patterns in feedforward network (FFN). Effects of heterogeneities both in parameters of neuronal excitability and synaptic delays are investigated systematically. Neuronal heterogeneity is found to modulate firing rates and spiking regularity by changing the excitability of the network. Synaptic delays are strongly related with desynchronized and synchronized firing patterns of the FFN, which indicate that synaptic delays may play a significant role in bridging rate coding and temporal coding. Furthermore, quasi-coherence resonance (quasi-CR) phenomenon is observed in the parameter domain of connection probability and delay-heterogeneity. All these phenomena above enable a detailed characterization of neuronal heterogeneity in FFN, which may play an indispensable role in reproducing the important properties of in vivo experiments.

scholarly journals Relative contribution of non-structural protein 1 in dengue pathogenesis

2020 ◽  
Author(s):  
Pei Xuan Lee ◽  
Donald Heng Rong Ting ◽  
Clement Peng Hee Boey ◽  
Eunice Tze Xin Tan ◽  
Janice Zuo Hui Chia ◽  
...  
Keyword(s):  
Critical Role ◽  
Health Concern ◽  
Structural Protein ◽  
Promising Candidate ◽  
Relative Contribution ◽  
Structural Region ◽  
Strain Dependent ◽  
Pro Inflammatory Cytokines

AbstractDengue is a major public health concern in the tropical and sub-tropical world with no effective treatment. The controversial live attenuated virus vaccine Dengvaxia has boosted the pursuit of sub-unit vaccine approaches, and the non-structural protein 1 (NS1) has recently emerged as a promising candidate. However, we found that NS1 immunization or passive transfer of NS1 antibodies failed to confer protection in symptomatic dengue mouse models using two non mouse-adapted DENV2 strains from the Cosmopolitan genotype that currently circulates in South-East Asia. Furthermore, exogenous administration of purified NS1 did not worsen in vivo vascular leakage in sub-lethally infected mice, thereby supporting that NS1 does not play a critical role in the pathogenesis of these DENV2 strains. Virus chimerization approaches indicated that the prME structural region, but not NS1, plays a critical role in driving in vivo fitness and virulence of the virus, through induction of key pro-inflammatory cytokines. This work highlights that the pathogenic role of NS1 is DENV strain-dependent, which warrants re-evaluation of NS1 as a universal dengue vaccine candidate.

scholarly journals Relative contribution of nonstructural protein 1 in dengue pathogenesis

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Pei Xuan Lee ◽  
Donald Heng Rong Ting ◽  
Clement Peng Hee Boey ◽  
Eunice Tze Xin Tan ◽  
Janice Zuo Hui Chia ◽  
...  
Keyword(s):  
Nonstructural Protein ◽  
Critical Role ◽  
Health Concern ◽  
Relative Contribution ◽  
Nonstructural Protein 1 ◽  
Structural Region ◽  
Strain Dependent ◽  
Highly Virulent

Dengue is a major public health concern in the tropical and subtropical world, with no effective treatment. The controversial live attenuated virus vaccine Dengvaxia has boosted the pursuit of subunit vaccine approaches, and nonstructural protein 1 (NS1) has recently emerged as a promising candidate. However, we found that NS1 immunization or passive transfer of NS1 antibodies failed to confer protection in symptomatic dengue mouse models using two non–mouse-adapted DENV2 strains that are highly virulent. Exogenous administration of purified NS1 also failed to worsen in vivo vascular leakage in sublethally infected mice. Neither method of NS1 immune neutralization changed the disease outcome of a chimeric strain expressing a vascular leak-potent NS1. Instead, virus chimerization involving the prME structural region indicated that these proteins play a critical role in driving in vivo fitness and virulence of the virus, through induction of key proinflammatory cytokines. This work highlights that the pathogenic role of NS1 is DENV strain dependent, which warrants reevaluation of NS1 as a universal dengue vaccine candidate.

scholarly journals Increased Human Wildtype Tau Attenuates Axonal Transport Deficits Caused by Loss of App in Mouse Models

2010 ◽  
Vol 4 ◽  
pp. MRI.S5237 ◽  
Author(s):  
Karen D.B. Smith ◽  
Erica Peethumnongsin ◽  
Han Lin ◽  
Hui Zheng ◽  
Robia G. Pautler
Keyword(s):  
Synaptic Plasticity ◽  
Axonal Transport ◽  
Mouse Models ◽  
Knockout Mice ◽  
Early Age ◽  
Axonal Elongation ◽  
Protein Tau ◽  
Manganese Enhanced Mri

Amyloid precursor protein (APP) is implicated in axonal elongation, synaptic plasticity, and axonal transport. However, the role of APP on axonal transport in conjunction with the microtubule associated protein tau continues to be debated. Here we measured in vivo axonal transport in APP knockout mice with Manganese Enhanced MRI (MEMRI) to determine whether APP is necessary for maintaining normal axonal transport. We also tested how overexpression and mutations of tau affect axonal transport in the presence or absence of APP. In vivo axonal transport reduced significantly in the absence of functional APP. Overexpression of human wildtype tau maintained normal axonal transport and resulted in a transient compensation of axonal transport deficits in the absence of APP. Mutant R406Wtau in combination with the absence of APP compounded axonal transport deficits and these deficits persisted with age. These results indicate that APP is necessary for axonal transport, and overexpression of human wildtype tau can compensate for the absence of APP at an early age.

scholarly journals Exon as well as intron sequences are cis-regulating elements for the mutually exclusive alternative splicing of the beta tropomyosin gene.

1990 ◽  
Vol 10 (10) ◽  
pp. 5036-5046 ◽  
Author(s):  
D Libri ◽  
M Goux-Pelletan ◽  
E Brody ◽  
M Y Fiszman
Keyword(s):  
Skeletal Muscle ◽  
Branch Point ◽  
Specific Pattern ◽  
Acceptor Site ◽  
Polypyrimidine Tract ◽  
Unusual Position ◽  
Cultured Myotubes ◽  
Characteristic Features

The beta tropomyosin gene contains two internal exons which are spliced in a mutually exclusive manner. Exon 6B is specifically included in the mature transcripts expressed in skeletal muscle or cultured myotubes, while exon 6A is a myoblast- or smooth muscle-specific exon. The intron between them, which is never spliced in normal conditions, contains two characteristic features: first, the unusual location of the branch point at position -105 from the acceptor, and second, the presence of a very long pyrimidine stretch upstream of the skeletal muscle exon. In this study we designed a number of sequence modifications to investigate the role of these two elements and of a computer-predicted secondary structure in the mutually exclusive splicing of the two exons. We found that mutations in the skeletal exon as well as in the upstream intron could change in vivo the tissue-specific pattern as well as the mutually exclusive character of the two exons. Our results suggest that the unusual position of the branch point does not prevent the utilization of exon 6B in myoblasts and that the region around the acceptor site of exon 6B and the polypyrimidine tract have an important role in this control. Last, we discuss the possible implications of secondary structures.

scholarly journals Contributions of Microglia to Structural Synaptic Plasticity

2013 ◽  
Vol 7 ◽  
pp. JEN.S11269 ◽  
Author(s):  
Kyung Ho Kim ◽  
Sung Min Son ◽  
Inhee Mook-Jung
Keyword(s):  
Synaptic Plasticity ◽  
Brain Cell ◽  
In Vivo Studies ◽  
Neural Function ◽  
Special Role ◽  
Neuronal Synapses ◽  
Total Brain ◽  
Synaptic Changes

Synaptic plasticity critically depends on reciprocal interactions between neurons and glia. Among glial cells, microglia represent approximately 10% of the total brain cell population serve as the brain's resident macrophage, and help to modulate neural activity. Because of their special role in the brain's immune response, microglia are involved in the pathological progression of neurodegenerative disorders such as Alzheimer's disease (AD). However, microglia also are surveyors of the brain's health and continuously contact dendritic spines to regulate structural synaptic changes. This review summarizes our current understanding of neuronal-microglial signals that affect neural function at the synapse. Here, we examine the role of microglia in neuronal synapses in pathological brains and specifically focus on in vivo studies using 2-photon microscopy. Furthermore, because the role of microglia in AD progression is controversial, we outline the interaction between neurons and microglia in pathological conditions such as AD.

Exon as well as intron sequences are cis-regulating elements for the mutually exclusive alternative splicing of the beta tropomyosin gene

1990 ◽  
Vol 10 (10) ◽  
pp. 5036-5046
Author(s):  
D Libri ◽  
M Goux-Pelletan ◽  
E Brody ◽  
M Y Fiszman
Keyword(s):  
Skeletal Muscle ◽  
Branch Point ◽  
Specific Pattern ◽  
Acceptor Site ◽  
Polypyrimidine Tract ◽  
Unusual Position ◽  
Cultured Myotubes ◽  
Characteristic Features

The beta tropomyosin gene contains two internal exons which are spliced in a mutually exclusive manner. Exon 6B is specifically included in the mature transcripts expressed in skeletal muscle or cultured myotubes, while exon 6A is a myoblast- or smooth muscle-specific exon. The intron between them, which is never spliced in normal conditions, contains two characteristic features: first, the unusual location of the branch point at position -105 from the acceptor, and second, the presence of a very long pyrimidine stretch upstream of the skeletal muscle exon. In this study we designed a number of sequence modifications to investigate the role of these two elements and of a computer-predicted secondary structure in the mutually exclusive splicing of the two exons. We found that mutations in the skeletal exon as well as in the upstream intron could change in vivo the tissue-specific pattern as well as the mutually exclusive character of the two exons. Our results suggest that the unusual position of the branch point does not prevent the utilization of exon 6B in myoblasts and that the region around the acceptor site of exon 6B and the polypyrimidine tract have an important role in this control. Last, we discuss the possible implications of secondary structures.

Assessment of the Relative Contribution of Different Protease Inhibitors to the Inhibition of Plasmin In Vivo

1993 ◽  
Vol 69 (02) ◽  
pp. 141-146 ◽  
Author(s):  
Marcel Levi ◽  
Dorina Roem ◽  
Angela M Kamp ◽  
Jan Paul de Boer ◽  
C Erik Hack ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Protease Inhibitors ◽  
Proteolytic Enzyme ◽  
Antithrombin Iii ◽  
C1 Inhibitor ◽  
Relative Contribution ◽  
Α2 Macroglobulin ◽  
Diffuse Intravascular Coagulation

SummaryIt has been shown that the most important inhibitor of plasmin is α2-antiplasmin, however, other protease inhibitors are able to inhibit this proteolytic enzyme as well. The contribution of the various protease inhibitors to the inhibition of plasmin in vivo has never been quantitatively assessed.To assess the relative contribution of the different protease inhibitors on the inhibition of plasmin we developed a series of sensitive immunoassays for the detection of complexes between plasmin and the protease inhibitors α2-antiplasmin, α2-macroglobulin, antithrombin III, α1antitrypsin and C1-inhibitor, utilizing monoclonal antibodies that are specifically directed against complexed protease inhibitors and a monoclonal antibody against plasmin.It was confirmed that α2-antiplasmin is the most important inhibitor of plasmin in vivo, however, complexes of plasmin with α2-macroglobulin, antithrombin III, α1antitrypsin- and C1-inhibitor were also detected. Particularly during activation of fibrinolysis complexes between plasmin and inhibitors other than α2-antiplasmin were detected. It was observed that during different situations the inhibition profile of plasmin was not constant e.g. in patients with diffuse intravascular coagulation plasma levels of plasmin-α1-antitrypsin and plasmin-C1-inhibitor were increased whereas in plasma from patients who were treated with thrombolytic agents complexes of plasmin with α2-macroglobulin and with antithrombin III were significantly elevated.In conclusion, we confirmed the important role of α2-antiplasmin in the inhibition of plasmin, however, in situations in which fibrinolysis is activated other protease inhibitors also account for the inhibition of plasmin in vivo. Further investigations to assess the role of the various protease inhibitors in the fibrinolytic system can be assisted by the assays described in this study.

scholarly journals Tyrosine phosphorylation of the AMPA receptor subunit GluA2 gates homeostatic synaptic plasticity

2020 ◽  
Vol 117 (9) ◽  
pp. 4948-4958 ◽  
Author(s):  
Adeline J. H. Yong ◽  
Han L. Tan ◽  
Qianwen Zhu ◽  
Alexei M. Bygrave ◽  
Richard C. Johnson ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Phosphorylation Site ◽  
Long Term Potentiation ◽  
Interacting Protein ◽  
Hebbian Plasticity ◽  
Term Potentiation ◽  
Ampa Receptor Subunit

Hebbian plasticity, comprised of long-term potentiation (LTP) and depression (LTD), allows neurons to encode and respond to specific stimuli; while homeostatic synaptic scaling is a counterbalancing mechanism that enables the maintenance of stable neural circuits. Both types of synaptic plasticity involve the control of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) abundance, which is modulated by AMPAR phosphorylation. To address the necessity of GluA2 phospho-Y876 in synaptic plasticity, we generated phospho-deficient GluA2 Y876F knock-in mice. We show that, while GluA2 phospho-Y876 is not necessary for Hebbian plasticity, it is essential for both in vivo and in vitro homeostatic upscaling. Bidirectional changes in GluA2 phospho-Y876 were observed during homeostatic scaling, with a decrease during downscaling and an increase during upscaling. GluA2 phospho-Y876 is necessary for synaptic accumulation of glutamate receptor interacting protein 1 (GRIP1), a crucial scaffold protein that delivers AMPARs to synapses, during upscaling. Furthermore, increased phosphorylation at GluA2 Y876 increases GluA2 binding to GRIP1. These results demonstrate that AMPAR trafficking during homeostatic upscaling can be gated by a single phosphorylation site on the GluA2 subunit.

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