scholarly journals Strength and duration of perisomatic GABAergic inhibition depend on distance between synaptically connected cells

2015 ◽  
Vol 112 (4) ◽  
pp. 1220-1225 ◽  
Author(s):  
Michael Strüber ◽  
Peter Jonas ◽  
Marlene Bartos
Keyword(s):  
Time Course ◽  
Principal Cell ◽  
Target Cells ◽  
Synaptic Inhibition ◽  
Gabaergic Inhibition ◽  
Large Neuron ◽  
Neuron Populations ◽  
Neuronal Network Model ◽  
Fast Spiking ◽  
Lower Contact

GABAergic perisoma-inhibiting fast-spiking interneurons (PIIs) effectively control the activity of large neuron populations by their wide axonal arborizations. It is generally assumed that the output of one PII to its target cells is strong and rapid. Here, we show that, unexpectedly, both strength and time course of PII-mediated perisomatic inhibition change with distance between synaptically connected partners in the rodent hippocampus. Synaptic signals become weaker due to lower contact numbers and decay more slowly with distance, very likely resulting from changes in GABAA receptor subunit composition. When distance-dependent synaptic inhibition is introduced to a rhythmically active neuronal network model, randomly driven principal cell assemblies are strongly synchronized by the PIIs, leading to higher precision in principal cell spike times than in a network with uniform synaptic inhibition.

CORTICOSTEROIDOGENESIS IN ISOLATED ADRENAL CELLS: EFFECT OF ADRENOCORTICOTROPHIC HORMONE, ADENOSINE 3′,5′-MONOPHOSPHATE AND β1–24ADRENOCORTICOTROPHIC HORMONE DIAZOTIZED TO POLYACRYLAMIDE

1972 ◽  
Vol 55 (1) ◽  
pp. 127-139 ◽  
Author(s):  
M. C. RICHARDSON ◽  
D. SCHULSTER
Keyword(s):  
Time Course ◽  
Biologically Active ◽  
Target Cells ◽  
Adrenal Cells ◽  
Active Peptides ◽  
Biologically Active Peptides ◽  
Normal Rat ◽  
Acth Concentration ◽  
A Cell ◽  
Competitive Protein Binding

SUMMARY A cell suspension was prepared from normal rat adrenal tissue by collagenase digestion of decapsulated adrenal glands. Corticosterone produced by these cells was assayed both by competitive protein binding and by radioimmunoassay (range: 0–1 ng; sensitivity: 30 pg). Before incubation, the medium and cells equivalent to one gland contained 27·7 ± 3·2 ng corticosterone which increased to 36·3 ± 7·0 ng corticosterone after 1 h of incubation. Although a normal sigmoid log dose—response curve was obtained using adrenocorticotrophin (ACTH) (ED50:1·2 × 10−4 i.u./ml), it was observed that log (ACTH concentration) was directly proportional to log (corticosterone produced) between 1 × 10−7 and 1 × 10−3 i.u. ACTH/ml. A similar linear relationship was demonstrated for the effect of adenosine 3′,5′-monophosphate on steroidogenesis. Time-course studies revealed that after addition of ACTH there was a definite lag (3 min) before onset of increased steroidogenesis; within 5 min a constant corticosterone production rate was achieved. β1–24 Adrenocorticotrophin was shown to retain its ability to stimulate steroidogenesis when diazotized to beads of polyacrylamide too large to enter cells. Evidence is provided that the activity of the β1–24 ACTH—polyacrylamide beads is not due to biologically active peptides cleaved from the complex. It is concluded that ACTH can stimulate steroidogenesis without entering its target cells.

scholarly journals Inhibitory Inputs to Hippocampal Interneurons Are Reorganized in Lis1 Mutant Mice

2009 ◽  
Vol 102 (2) ◽  
pp. 648-658 ◽  
Author(s):  
Daniel L. Jones ◽  
Scott C. Baraban
Keyword(s):  
Hippocampal Slices ◽  
Mean Amplitude ◽  
Mutant Mice ◽  
Synaptic Inhibition ◽  
Brain Malformation ◽  
Synaptic Excitation ◽  
Decay Times ◽  
Hippocampal Area ◽  
Fast Spiking ◽  
Selective Displacement

Epilepsy and brain malformation are commonly associated with excessive synaptic excitation and decreased synaptic inhibition of principal neurons. However, few studies have examined the state of synaptic inhibition of interneurons in an epileptic, malformed brain. We analyzed inhibitory inputs, mediated by γ-aminobutyric acid (GABA), to hippocampal interneurons in a mouse model of type 1 lissencephaly, a neurological disorder linked with severe seizures and brain malformation. In the disorganized hippocampal area CA1 of Lis1+/− mice, we initially observed a selective displacement of fast-spiking, parvalbumin-positive basket-type interneurons from stratum oriens (SO) locations to s. radiatum and s. lacunosum-moleculare (R/LM). Next, we recorded spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) onto visually identified interneurons located in SO or R/LM of Lis1+/− mice and age-matched littermate controls. We observed significant, layer-specific reorganizations in GABAergic inhibition of interneurons in Lis1 mutant mice. Spontaneous IPSC frequency onto SO interneurons was significantly increased in hippocampal slices from Lis1+/− mice, whereas mIPSC mean amplitude onto these interneurons was significantly decreased. In addition, the weighted decay times of sIPSCs and mIPSCs were significantly increased in R/LM interneurons. Taken together, these findings illustrate the extensive redistribution and reorganization of inhibitory connections between interneurons that can take place in a malformed brain.

scholarly journals STUDIES ON CELL-MEDIATED IMMUNITY TO LYMPHOCYTIC CHORIOMENINGITIS VIRUS IN MICE

1973 ◽  
Vol 137 (6) ◽  
pp. 1511-1525 ◽  
Author(s):  
Ole Marker ◽  
Mogens Volkert
Keyword(s):  
Time Course ◽  
Underlying Mechanism ◽  
Cell Interaction ◽  
Lymphocytic Choriomeningitis ◽  
Lymphoid Cells ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Sharp Maximum ◽  
Direct Cell

A large amount of experimental evidence has already been presented indicating the great importance of the cell-mediated immunity in the pathogenesis of the LCM virus infection in mice. In this laboratory a method which makes it possible to measure this cellular immunity quantitatively in vitro has been developed. The method is based on the determination of the radioisotope released after the interaction between specifically sensitized lymphocytes and syngeneic 1Cr-labeled LCM virus-infected target cells. By using this technique the time-course of the cell-mediated immunity has been established in acutely infected mice and in virus carriers adoptively immunized with syngeneic sensitized lymphocytes. Lymphocytes from acutely infected mice showed a strong lysing effect on the target cells, with a sharp maximum at about the 9th day after infection. The cell-mediated immunity in adoptively immunized virus carrier mice showed the same time-course, but in these animals the lytic effect of the lymphoid cells was considerably less pronounced. Lymphocytes from untreated virus carriers did not, however, have any effect on the target cells, and in these animals it was not possible to demonstrate any evidence of enhancing antibodies, In experiments employing serial dilutions of sensitized lymphocytes in normal cells a direct linear relationship between the number of sensitized lymphocytes and target cell destruction was found. These experiments seem to indicate that the underlying mechanism in the cytotoxic reaction is a direct cell-to-cell interaction.

scholarly journals Serotonergic modulation of swimming speed in the pteropod mollusc Clione limacina. III. Cerebral neurons.

1995 ◽  
Vol 198 (4) ◽  
pp. 917-930 ◽  
Author(s):  
R A Satterlie ◽  
T P Norekian
Keyword(s):  
Motor Neurons ◽  
Time Course ◽  
Neuron Activity ◽  
Target Cells ◽  
Cellular Mechanisms ◽  
Cycle Frequency ◽  
Course Of Action ◽  
Cell Groups ◽  
Cerebral Neurons ◽  
Clione Limacina

Swim acceleration in Clione limacina can occur via central inputs to pattern generator interneurons and motor neurons and through peripheral inputs to the swim musculature. In the previous paper, peripheral modulation of the swim muscles was shown to increase wing contractility. In the present paper, central inputs are described that trigger an increase in swim frequency and an increase in motor neuron activity. In dissected preparations, spontaneous acceleration from slow to fast swimming included an increase in the cycle frequency, a baseline depolarization in the swim interneurons and an increase in the intensity of motoneuron firing. Similar effects could be elicited by bath application of 10(-5) mol l-1 serotonin. Two clusters of cerebral serotonin-immunoreactive interneurons were found to produce acceleration of swimming accompanied by changes in neuronal activity. Posterior cluster neurons triggered an increase in swim frequency, depolarization of the swim interneurons, an increase in general excitor motoneuron activity and activation of type 12 interneurons and pedal peripheral modulatory neurons. Cells from the anterior cerebral cluster also increased swim frequency, increased activity in the swim motoneurons and activated type 12 interneurons, pedal peripheral modulatory neurons and the heart excitor neuron. The time course of action of the anterior cluster neurons did not greatly outlast the duration of spike activity, while that of the posterior cluster neurons typically outlasted burst duration. It appears that the two discrete clusters of serotonin-immunoreactive neurons have similar, but not identical, effects on swim neurons, raising the possibility that the two serotonergic cell groups modulate the same target cells through different cellular mechanisms.

scholarly journals Cyclic, condition-independent activity in primary motor cortex predicts corrective movement behavior

2018 ◽  
Author(s):  
Adam G. Rouse ◽  
Marc H. Schieber ◽  
Sridevi V. Sarma
Keyword(s):  
Motor Cortex ◽  
Neural Activity ◽  
Time Course ◽  
Primary Motor Cortex ◽  
Reaching Movements ◽  
Movement Behavior ◽  
Cyclic Activity ◽  
Cyclic Condition ◽  
Neuron Populations ◽  
Optimizing Control

AbstractReaching movements have previously been observed to have large condition-independent neural activity and cyclic neural dynamics. A new precision center-out task was used to test whether cyclic neural activity in the primary motor cortex (M1) occurred not only during initial reaching movements but also during subsequent corrective movements. Corrective movements were observed to be discrete with a time course and bell-shaped speed profile similar to the initial movements. Cyclic trajectories identified in the condition-independent neural activity were similar for initial and corrective submovements. The phase of the cyclic condition-independent neural activity predicted when peak movement speeds occurred, even when the subject made multiple corrective movements. Rather than being controlled as continuations of the initial reach, a discrete cycle of motor cortex activity encodes each corrective submovement.Significance StatementDuring a precision center-out task, initial and subsequent corrective movements occur as discrete submovements with bell-shaped speed profiles. A cycle of condition-independent activity in primary motor cortex neuron populations corresponds to each submovement whether initial or corrective, such that the phase of this cyclic activity predicts the time of peak speed. These submovements accompanied by cyclic neural activity offer important clues into how the we successfully execute precise, corrective reaching movements and may have implications for optimizing control of brain-computer interfaces.

scholarly journals Bacterial Lipopolysaccharide Inhibits Dengue Virus Infection of Primary Human Monocytes/Macrophages by Blockade of Virus Entry via a CD14-Dependent Mechanism

1999 ◽  
Vol 73 (4) ◽  
pp. 2650-2657 ◽  
Author(s):  
Yun-Chi Chen ◽  
Sheng-Yuan Wang ◽  
Chwan-Chuen King
Keyword(s):  
Dengue Virus ◽  
Time Course ◽  
Time Lag ◽  
Inhibitory Effect ◽  
Bacterial Lipopolysaccharide ◽  
Target Cells ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Cytokines And Chemokines ◽  
Viral Adsorption

ABSTRACT Monocytes/macrophages (MO/Mφ) are the major target cells for both dengue virus (DV) and bacterial lipopolysaccharide (LPS), and the aim of this study was to define their interactions. We had found that LPS markedly suppressed DV infection of primary human MO/Mφ when it was added to cultures prior to or together with, but not after, viral adsorption. The inhibitory effect of LPS was direct and specific and was not mediated by LPS-induced secretion of cytokines and chemokines such as tumor necrosis factor alpha, interleukin-1β (IL-1β), IL-6, IL-8, IL-12, alpha interferon, MIP-1α, and RANTES. In fact, productive DV infection was not blocked but was just postponed by LPS, with a time lag equal to one viral replication cycle. Time course studies demonstrated that LPS was only effective in suppressing DV infection of MO/Mφ that had not been previously exposed to the virus. At various time points after viral adsorption, the level of unbound viruses that remained free in the culture supernatants of LPS-pretreated cultures was much higher than that of untreated controls. These observations suggest that the LPS-induced suppression of DV replication was at the level of virus attachment and/or entry. Blockade of the major LPS receptor, CD14, with monoclonal antibodies MY4 or MoS39 failed to inhibit DV infection but could totally abrogate the inhibitory effect of LPS. Moreover, human serum could significantly enhance the LPS-induced DV suppression in a CD14-dependent manner, indicating that the “binding” of LPS to CD14 was critical for the induction of virus inhibition. Taken together, our results suggest that LPS blocked DV entry into human MO/Mφ via its receptor CD14 and that a CD14-associated cell surface structure may be essential for the initiation of a DV infection.

scholarly journals A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression

2015 ◽  
Vol 59 (9) ◽  
pp. 5388-5395 ◽  
Author(s):  
Mohamed A. Kamal ◽  
Ronald Gieschke ◽  
Annabelle Lemenuel-Diot ◽  
Catherine A. A. Beauchemin ◽  
Patrick F. Smith ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Time Course ◽  
Disease Model ◽  
Virus Production ◽  
Target Cells ◽  
Initiation Time ◽  
Viral Shedding ◽  
Therapy Initiation ◽  
Infected Cells ◽  
Virus Strains

ABSTRACTA population drug-disease model was developed to describe the time course of influenza virus with and without oseltamivir treatment and to investigate opportunities for antiviral combination therapy. Data included viral titers from 208 subjects, across 4 studies, receiving placebo and oseltamivir at 20 to 200 mg twice daily for 5 days. A 3-compartment mathematical model, comprising target cells infected at rate β, free virus produced at ratepand cleared at ratec, and infected cells cleared at rate δ, was implemented in NONMEM with an inhibitory Hill function on virus production (p), accounting for the oseltamivir effect. In congruence with clinical data, the model predicts that the standard 75-mg regimen initiated 2 days after infection decreased viral shedding duration by 1.5 days versus placebo; the 150-mg regimen decreased shedding by an additional average 0.25 day. The model also predicts that initiation of oseltamivir sooner postinfection, specifically at day 0.5 or 1, results in proportionally greater decreases in viral shedding duration of 5 and 3.5 days, respectively. Furthermore, the model suggests that combining oseltamivir (acting to subdue virus production rate) with an antiviral whose activity decreases viral infectivity (β) results in a moderate additive effect dependent on therapy initiation time. In contrast, the combination of oseltamivir with an antiviral whose activity increases viral clearance (c) shows significant additive effects independent of therapy initiation time. The utility of the model for investigating the pharmacodynamic effects of novel antivirals alone or in combination on emergent influenza virus strains warrants further investigation.

scholarly journals Molecular Biology of Escherichia coli Shiga Toxins’ Effects on Mammalian Cells

Toxins ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 345 ◽  
Author(s):  
Christian Menge
Keyword(s):  
Escherichia Coli ◽  
Mammalian Cells ◽  
Time Course ◽  
Current Knowledge ◽  
Enterohemorrhagic Escherichia Coli ◽  
Mammalian Host ◽  
Target Cells ◽  
Cellular Functions ◽  
Comprehensive Overview ◽  
Shiga Toxins

Shiga toxins (Stxs), syn. Vero(cyto)toxins, are potent bacterial exotoxins and the principal virulence factor of enterohemorrhagic Escherichia coli (EHEC), a subset of Shiga toxin-producing E. coli (STEC). EHEC strains, e.g., strains of serovars O157:H7 and O104:H4, may cause individual cases as well as large outbreaks of life-threatening diseases in humans. Stxs primarily exert a ribotoxic activity in the eukaryotic target cells of the mammalian host resulting in rapid protein synthesis inhibition and cell death. Damage of endothelial cells in the kidneys and the central nervous system by Stxs is central in the pathogenesis of hemolytic uremic syndrome (HUS) in humans and edema disease in pigs. Probably even more important, the toxins also are capable of modulating a plethora of essential cellular functions, which eventually disturb intercellular communication. The review aims at providing a comprehensive overview of the current knowledge of the time course and the consecutive steps of Stx/cell interactions at the molecular level. Intervention measures deduced from an in-depth understanding of this molecular interplay may foster our basic understanding of cellular biology and microbial pathogenesis and pave the way to the creation of host-directed active compounds to mitigate the pathological conditions of STEC infections in the mammalian body.

Regulation of the NMDA Component of EPSPs by Different Components of Postsynaptic GABAergic Inhibition: Computer Simulation Analysis in Piriform Cortex

1997 ◽  
Vol 78 (5) ◽  
pp. 2546-2559 ◽  
Author(s):  
A. Kapur ◽  
W. W. Lytton ◽  
K. L. Ketchum ◽  
L. B. Haberly
Keyword(s):  
Computer Simulation ◽  
Time Course ◽  
Simulation Analysis ◽  
Slow Component ◽  
Piriform Cortex ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Companion Paper ◽  
System Stability ◽  
Gabaergic Inhibition

Kapur, A., W. W. Lytton, K. L. Ketchum, and L. B. Haberly. Regulation of the NMDA component of EPSPs by different components of postsynaptic GABAergic inhibition: computer simulation analysis in piriform cortex. J. Neurophysiol. 78: 2546–2559, 1997. Physiological analysis in the companion paper demonstrated that γ-aminobutyric acid-A (GABAA)-mediated inhibition in piriform cortex is generated by circuits that are largely independent in apical dendritic and somatic regions of pyramidal cells and that GABAA-mediated inhibitory postsynaptic currents (IPSCs) in distal dendrites have a slower time course than those in the somatic region. This study used modeling methods to explore these characteristics of GABAA-mediated inhibition with respect to regulation of the N-methyl-d-aspartate (NMDA) component of excitatory postsynaptic potentials. Such regulation is relevant to understanding NMDA-dependent long-term potentiation (LTP) and the integration of repetitive synaptic inputs that can activate the NMDA component as well as pathological processes that can be activated by overexpression of the NMDA component. A working hypothesis was that the independence and differing properties of IPSCs in apical dendritic and somatic regions provide a means whereby the NMDA component and other dendritic processes can be controlled by way of GABAergic tone without substantially altering system excitability. The analysis was performed on a branched compartmental model of a pyramidal cell in piriform cortex constructed with physiological and anatomic data derived by whole cell patch recording. Simulations with the model revealed that NMDA expression is more effectively blocked by the slow GABAA component than the fast. Because the slow component is present in greater proportion in apical dendritic than somatic regions, this characteristic would increase the capacity of dendritic IPSCs to regulate NMDA-mediated processes. The simulations further revealed that somatic-region GABAergic inhibition can regulate the generation of action potentials with little effect on the NMDA component generated by afferent fibers in apical dendrites. As a result, if expression of the NMDA component or other dendritic processes were enabled by selective block of dendritic inhibition, for example, by centrifugal fiber systems that may regulate learning and memory, the somatic-region IPSC could preserve system stability through feedback regulation of firing without counteracting the effect of the dendritic-region block. Simulations with paired inputs revealed that the dendritic GABAA-mediated IPSC can regulate the extent to which a strong excitatory input facilitates the NMDA component of a concurrent weak input, providing a possible mechanism for control of “associative LTP” that has been demonstrated in this system. Postsynaptic GABAB-mediated inhibition had less effect on the NMDA component than either the fast or slow GABAA components. Depolarization from a concomitant α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component also was found to have comparatively little effect on current through the NMDA channel because of its brief time course.

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