scholarly journals Kcns3 Deficiency Disrupts Parvalbumin Neuron Physiology in Mouse Prefrontal Cortex: Implications for the pathophysiology of schizophrenia

2020 ◽  
Author(s):  
Takeaki Miyamae ◽  
Takanori Hashimoto ◽  
Monica Abraham ◽  
Rika Kawabata ◽  
Sho Koshikizawa ◽  
...  
Keyword(s):  
Computational Model ◽  
Cell Model ◽  
Gamma Oscillations ◽  
Spike Trains ◽  
Repetitive Firing ◽  
Mrna Levels ◽  
Gene Encoding ◽  
Gamma Frequency ◽  
Channel Inactivation ◽  
Deficient Mice

AbstractThe unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively express Kcns3, the gene encoding Kv9.3 subunits, suggesting that Kcns3 expression is critical for the FS phenotype. KCNS3 expression is lower in PV neurons in schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. We therefore assessed the role of Kv9.3 subunits in PV neuron function by combining gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex of Kcns3-deficient miceKcns3 mRNA levels were ~50% lower in cortical PV neurons from Kcns3-deficient relative to wildtype mice. While silent per se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na+ channel inactivation, possibly due to a smaller afterhyperpolarization. As in the computational model, PV basket cells (PVBCs) from Kcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing, and smaller afterhyperpolarization. Moreover, Kcns3 deficiency impaired the recruitment of PVBCs by stimuli mimicking synaptic input during cortical UP states, which elicited bursts of spikes at gamma frequency. Our data suggest that Kv9.3 subunits are critical for PVBC physiology, and that KCNS3 deficiency in schizophrenia may impair the substrate of gamma oscillations.Significance statementIn the neocortex, Kcns3, the gene encoding voltage-dependent potassium (Kv) channel subunits Kv9.3, is selectively expressed by parvalbumin-positive (PV) neurons. Moreover, KCNS3 expression is decreased in PV neurons in schizophrenia. Kv 9.3 subunits are believed to amplify the current mediated by Kv2.1 subunits, however Kv9.3 function has not been investigated in PV cells.Here, simulations in a computational model and electrophysiological experiments with Kcns3-deficient mice revealed that Kcns3 deficiency disrupts repetitive firing in cortical PV neurons, possibly enhancing Na+ channel inactivation, and particularly with stimuli eliciting firing at gamma frequency band (30-80Hz). Our results suggest that Kv9.3 subunits are essential for PV neuron electrophysiology and that KCNS3 deficiency likely contributes to PV neuron dysfunction and gamma oscillation impairments in schizophrenia.

Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion

2012 ◽  
Vol 48 (2) ◽  
pp. 151-158 ◽  
Author(s):  
Hongjie Zhang ◽  
Jing Li ◽  
Xiangying Liang ◽  
Yun Luo ◽  
Ke Zen ◽  
...  
Keyword(s):  
Cell Model ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Mrna Levels ◽  
Incretin Hormone ◽  
Mucosal Layer ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Deficient Mice

It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI-H716 cells, a well-characterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7–36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion.

scholarly journals The ionic mechanism of gamma resonance in rat striatal fast-spiking neurons

2011 ◽  
Vol 106 (6) ◽  
pp. 2936-2949 ◽  
Author(s):  
Giuseppe Sciamanna ◽  
Charles J. Wilson
Keyword(s):  
Firing Rate ◽  
Firing Pattern ◽  
Field Potential ◽  
Gamma Oscillations ◽  
Repetitive Firing ◽  
Spike Threshold ◽  
Gamma Frequency ◽  
Subthreshold Oscillations ◽  
Fast Spiking

Striatal fast-spiking (FS) cells in slices fire in the gamma frequency range and in vivo are often phase-locked to gamma oscillations in the field potential. We studied the firing patterns of these cells in slices from rats ages 16–23 days to determine the mechanism of their gamma resonance. The resonance of striatal FS cells was manifested as a minimum frequency for repetitive firing. At rheobase, cells fired a doublet of action potentials or doublets separated by pauses, with an instantaneous firing rate averaging 44 spikes/s. The minimum rate for sustained firing was also responsible for the stuttering firing pattern. Firing rate adapted during each episode of firing, and bursts were terminated when firing was reduced to the minimum sustainable rate. Resonance and stuttering continued after blockade of Kv3 current using tetraethylammonium (0.1–1 mM). Both gamma resonance and stuttering were strongly dependent on Kv1 current. Blockade of Kv1 channels with dendrotoxin-I (100 nM) completely abolished the stuttering firing pattern, greatly lowered the minimum firing rate, abolished gamma-band subthreshold oscillations, and slowed spike frequency adaptation. The loss of resonance could be accounted for by a reduction in potassium current near spike threshold and the emergence of a fixed spike threshold. Inactivation of the Kv1 channel combined with the minimum firing rate could account for the stuttering firing pattern. The resonant properties conferred by this channel were shown to be adequate to account for their phase-locking to gamma-frequency inputs as seen in vivo.

scholarly journals Reduced K+ Channel Inactivation, Spike Broadening, and After-Hyperpolarization in Kvβ1.1-Deficient Mice with Impaired Learning

1998 ◽  
Vol 5 (4) ◽  
pp. 257-273 ◽  
Author(s):  
Karl Peter Giese ◽  
Johan F. Storm ◽  
Dirk Reuter ◽  
Nikolai B. Fedorov ◽  
Li-Rong Shao ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Physiological Role ◽  
Neuronal Firing ◽  
Repetitive Firing ◽  
K Channel ◽  
Frequency Dependent ◽  
Channel Inactivation ◽  
Type K ◽  
Preference Task ◽  
Deficient Mice

A-type K+ channels are known to regulate neuronal firing, but their role in repetitive firing and learning in mammals is not well characterized. To determine the contribution of the auxiliary K+ channel subunit Kvβ1.1 to A-type K+ currents and to study the physiological role of A-type K+ channels in repetitive firing and learning, we deleted the Kvβ1.1 gene in mice. The loss of Kvβ1.1 resulted in a reduced K+ current inactivation in hippocampal CA1 pyramidal neurons. Furthermore, in the mutant neurons, frequency-dependent spike broadening and the slow afterhyperpolarization (sAHP) were reduced. This suggests that Kvβ1.1-dependent A-type K+ channels contribute to frequency-dependent spike broadening and may regulate the sAHP by controlling Ca2+ influx during action potentials. The Kvβ1.1-deficient mice showed normal synaptic plasticity but were impaired in the learning of a water maze test and in the social transmission of food preference task, indicating that the Kvβ1.1 subunit contributes to certain types of learning and memory.

scholarly journals Influence of NMDA and GABA synaptic dysfunction on the evoked gamma oscillations in a computational model of schizophrenia

Biologija ◽  
2017 ◽  
Vol 63 (2) ◽  
Author(s):  
Rokas Jackevičius ◽  
Bruce P. Graham ◽  
Aušra Saudargienė
Keyword(s):  
Neural Network ◽  
Computational Modeling ◽  
Computational Model ◽  
Time Constant ◽  
Gamma Oscillations ◽  
Synaptic Dysfunction ◽  
Spiking Neural Network ◽  
Gamma Frequency ◽  
Gated Channel ◽  
Fast Spiking

Background. Schizophrenia is a psychiatric disorder which is characterized by delusions and hallucinations, and affects thoughts, behaviour and emotions. Major neuronal degeneration is not observed in schizophrenic patients, but abnormalities in cortical circuits are present. These abnormalities are reflected in impaired EEG gamma frequency (30–80 Hz), being crucial for many processes including sensation, perception, working memory, and attention. NMDA and GABA synaptic dysfunction is proposed as one of the possible mechanisms underlying the gamma oscillatory deficits in schizophrenia. Materials and Methods. We used a computational modeling approach to investigate the joint influence of NMDA and GABA synaptic dysfunction on gamma oscillations in cortex. We employed a computational model of a spiking neural network composed of 800 pyramidal neurons, 150 regular-spiking interneurons, and 50 fast-spiking interneurons. All cells were randomly interconnected. Network neurons received independent Poisson noise input at 4 Hz and 40 Hz drive excitatory stimulation. Fast-spiking interneuron GABA receptor-gated channel time constant was increased and NMDA receptor-gated channel synaptic conductance was decreased to represent synaptic dysfunction in schizophrenia. Results. Reducing NMDA conductance enhanced gamma power, and increasing decay time constant of GABA receptorgated channel attenuated gamma generation in a network. The effect of synaptic GABA alteration was more profound. Conclusions. NMDA and GABA synaptic dysfunction leads to the impaired gamma frequency oscillations in a spiking neural network of cortex. Computational modeling approach is a powerful tool to understand complex non-linear dynamical systems and intrinsic mechanisms of neuronal network activity in healthy and diseased brain.

Metallothionein gene expression and secretion in white adipose tissue

2000 ◽  
Vol 279 (6) ◽  
pp. R2329-R2335 ◽  
Author(s):  
Paul Trayhurn ◽  
Jacqueline S. Duncan ◽  
Anne M. Wood ◽  
John H. Beattie
Keyword(s):  
Gene Expression ◽  
Molecular Weight ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Stromal Vascular Fraction ◽  
Low Molecular Weight ◽  
Secretory Product ◽  
Mrna Levels ◽  
Gene Encoding ◽  
Adrenoceptor Agonist

White adipose tissue (WAT) has been examined to determine whether the gene encoding metallothionein (MT), a low-molecular-weight stress response protein, is expressed in the tissue and whether MT may be a secretory product of adipocytes. The MT-1 gene was expressed in epididymal WAT, with MT-1 mRNA levels being similar in lean and obese ( ob/ ob) mice. MT-1 mRNA was found in each of the main adipose tissue sites (epididymal, perirenal, omental, subcutaneous), and there was no major difference between depots. Separation of adipocytes from the stromal-vascular fraction of WAT indicated that the MT gene (MT-1 and MT-2) was expressed in adipocytes themselves. Treatment of mice with zinc had no effect on MT-1 mRNA levels in WAT, despite strong induction of MT-1 expression in the liver. MT-1 gene expression in WAT was also unaltered by fasting or norepinephrine. However, administration of a β3-adrenoceptor agonist, BRL-35153A, led to a significant increase in MT-1 mRNA. On differentiation of fibroblastic preadipocytes to adipocytes in primary culture, MT was detected in the medium, suggesting that the protein may be secreted from WAT. It is concluded that WAT may be a significant site of MT production; within adipocytes, MT could play an antioxidant role in protecting fatty acids from damage.

scholarly journals Properties of precise firing synchrony between synaptically coupled cortical interneurons depend on their mode of coupling

2015 ◽  
Vol 114 (1) ◽  
pp. 624-637 ◽  
Author(s):  
Hang Hu ◽  
Ariel Agmon
Keyword(s):  
Firing Rate ◽  
Electrical Coupling ◽  
Gamma Oscillations ◽  
Inhibitory Synapses ◽  
Data Set ◽  
Temporal Precision ◽  
Gamma Frequency ◽  
Rate Dependent ◽  
Cortical Interneurons

Precise spike synchrony has been widely reported in the central nervous system, but its functional role in encoding, processing, and transmitting information is yet unresolved. Of particular interest is firing synchrony between inhibitory cortical interneurons, thought to drive various cortical rhythms such as gamma oscillations, the hallmark of cognitive states. Precise synchrony can arise between two interneurons connected electrically, through gap junctions, chemically, through fast inhibitory synapses, or dually, through both types of connections, but the properties of synchrony generated by these different modes of connectivity have never been compared in the same data set. In the present study we recorded in vitro from 152 homotypic pairs of two major subtypes of mouse neocortical interneurons: parvalbumin-containing, fast-spiking (FS) interneurons and somatostatin-containing (SOM) interneurons. We tested firing synchrony when the two neurons were driven to fire by long, depolarizing current steps and used a novel synchrony index to quantify the strength of synchrony, its temporal precision, and its dependence on firing rate. We found that SOM-SOM synchrony, driven solely by electrical coupling, was less precise than FS-FS synchrony, driven by inhibitory or dual coupling. Unlike SOM-SOM synchrony, FS-FS synchrony was strongly firing rate dependent and was not evident at the prototypical 40-Hz gamma frequency. Computer simulations reproduced these differences in synchrony without assuming any differences in intrinsic properties, suggesting that the mode of coupling is more important than the interneuron subtype. Our results provide novel insights into the mechanisms and properties of interneuron synchrony and point out important caveats in current models of cortical oscillations.

Control of mRNA turnover as a mechanism of glucose repression in Saccharomyces cerevisiae

1992 ◽  
Vol 12 (7) ◽  
pp. 2941-2948
Author(s):  
A Lombardo ◽  
G P Cereghino ◽  
I E Scheffler
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Succinate Dehydrogenase ◽  
Half Life ◽  
Glucose Repression ◽  
Promoter Sequence ◽  
Regulatory Elements ◽  
Mrna Levels ◽  
Protein Subunit ◽  
Gene Encoding ◽  
Regulatory Complex

We have examined the expression of the gene encoding the iron-protein subunit (Ip) of succinate dehydrogenase in Saccharomyces cerevisiae. The gene had been cloned by us and shown to be subject to glucose regulation (A. Lombardo, K. Carine, and I. E. Scheffler, J. Biol. Chem. 265:10419-10423, 1990). We discovered that a significant part of the regulation of the Ip mRNA levels by glucose involves the regulation of the turnover rate of this mRNA. In the presence of glucose, the half-life appears to be less than 5 min, while in glycerol medium, the half-life is greater than 60 min. The gene is also regulated transcriptionally by glucose. The upstream promoter sequence appeared to have four regulatory elements with consensus sequences shown to be responsible for the interaction with the HAP2/3/4 regulatory complex. A deletion analysis has shown that the two distal elements are redundant. These measurements were carried out by Northern (RNA) analyses of Ip mRNA transcripts as well as by assays of beta-galactosidase activity in cells carrying constructs of the Ip promoter linked to the lacZ coding sequence. These observations on the regulation of mRNA stability were also extended to the mRNA of the flavoprotein subunit of succinate dehydrogenase and in some experiments of iso-1-cytochrome c.

scholarly journals Registered report: Transcriptional amplification in tumor cells with elevated c-Myc

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
David Blum ◽  
Haiping Hao ◽  
Michael McCarthy ◽  
Keyword(s):  
Gene Expression ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Cell Model ◽  
Scientific Research ◽  
Digital Gene Expression ◽  
Open Science ◽  
Large Set ◽  
Mrna Levels ◽  
Transcriptional Amplification

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered report describes the proposed replication plan of key experiments from ‘Transcriptional amplification in tumor cells with elevated c-Myc’ by <xref ref-type="bibr" rid="bib5">Lin et al. (2012)</xref>, published in Cell in 2012. The experiments that will be replicated are those reported in Figures 3E and 3F. In these experiments, elevated levels of c-Myc in the P493-6 cell model of Burkitt's lymphoma results in an increase of the total level of RNA using UV/VIS spectrophotometry (Figure 3E; <xref ref-type="bibr" rid="bib5">Lin et al., 2012</xref>) and on the mRNA levels/cell for a large set of genes using digital gene expression technology (Figure 3F; <xref ref-type="bibr" rid="bib5">Lin et al., 2012</xref>). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published in eLife.

scholarly journals Eosinophil Deficiency Compromises Lung Defense against Aspergillus fumigatus

2013 ◽  
Vol 82 (3) ◽  
pp. 1315-1325 ◽  
Author(s):  
Lauren M. Lilly ◽  
Michaella Scopel ◽  
Michael P. Nelson ◽  
Ashley R. Burg ◽  
Chad W. Dunaway ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Cell Contact ◽  
Mrna Levels ◽  
Colony Stimulating Factor ◽  
Content Type ◽  
Eosinophil Peroxidase ◽  
Stimulating Factor ◽  
Deficient Mice

ABSTRACTExposure to the moldAspergillus fumigatusmay result in allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, or invasive aspergillosis (IA), depending on the host's immune status. Neutrophil deficiency is the predominant risk factor for the development of IA, the most life-threatening condition associated withA. fumigatusexposure. Here we demonstrate that in addition to neutrophils, eosinophils are an important contributor to the clearance ofA. fumigatusfrom the lung. AcuteA. fumigatuschallenge in normal mice induced the recruitment of CD11b+Siglec F+Ly-6GloLy-6CnegCCR3+eosinophils to the lungs, which was accompanied by an increase in lungEpx(eosinophil peroxidase) mRNA levels. Mice deficient in the transcription factor dblGATA1, which exhibit a selective deficiency in eosinophils, demonstrated impairedA. fumigatusclearance and evidence of germinating organisms in the lung. Higher burden correlated with lower mRNA expression ofEpx(eosinophil peroxidase) andPrg2(major basic protein) as well as lower interleukin 1β (IL-1β), IL-6, IL-17A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and CXCL1 levels. However, examination of lung inflammatory cell populations failed to demonstrate defects in monocyte/macrophage, dendritic cell, or neutrophil recruitment in dblGATA1-deficient mice, suggesting that the absence of eosinophils in dlbGATA1-deficient mice was the sole cause of impaired lung clearance. We show that eosinophils generated from bone marrow have potent killing activity againstA. fumigtausin vitro, which does not require cell contact and can be recapitulated by eosinophil whole-cell lysates. Collectively, our data support a role for eosinophils in the lung response afterA. fumigatusexposure.

A Computational Model as Neurodecoder Based on Synchronous Oscillation in the Visual Cortex

2003 ◽  
Vol 15 (10) ◽  
pp. 2399-2418 ◽  
Author(s):  
Zhao Songnian ◽  
Xiong Xiaoyun ◽  
Yao Guozheng ◽  
Fu Zhi
Keyword(s):  
Visual Cortex ◽  
Computational Model ◽  
Visual Information ◽  
Spike Trains ◽  
Spike Timing ◽  
Contour Detection ◽  
System Level ◽  
Neuronal Spike ◽  
Neuronal Spike Trains ◽  
External Stimuli

Based on synchronized responses of neuronal populations in the visual cortex to external stimuli, we proposed a computational model consisting primarily of a neuronal phase-locked loop (NPLL) and multiscaled operator. The former reveals the function of synchronous oscillations in the visual cortex. Regardless of which of these patterns of the spike trains may be an average firing-rate code, a spike-timing code, or a rate-time code, the NPLL can decode original visual information from neuronal spike trains modulated with patterns of external stimuli, because a voltage-controlled oscillator (VCO), which is included in the NPLL, can precisely track neuronal spike trains and instantaneous variations, that is, VCO can make a copy of an external stimulus pattern. The latter, however, describes multi-scaled properties of visual information processing, but not merely edge and contour detection. In this study, in which we combined NPLL with a multiscaled operator and maximum likelihood estimation, we proved that the model, as a neurodecoder, implements optimum algorithm decoding visual information from neuronal spike trains at the system level. At the same time, the model also obtains increasingly important supports, which come from a series of experimental results of neurobiology on stimulus-specific neuronal oscillations or synchronized responses of the neuronal population in the visual cortex. In addition, the problem of how to describe visual acuity and multiresolution of vision by wavelet transform is also discussed. The results indicate that the model provides a deeper understanding of the role of synchronized responses in decoding visual information.

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