Tonically Balancing Intracortical Excitation and Inhibition by GABAergic Gliotransmission

2014 ◽  
Vol 26 (8) ◽  
pp. 1690-1716 ◽  
Author(s):  
Meihong Zheng ◽  
Takami Matsuo ◽  
Ai Miyamoto ◽  
Osamu Hoshino
Keyword(s):  
Extracellular Space ◽  
Plasma Membranes ◽  
Sensory Information ◽  
Inhibitory Mechanism ◽  
Neuronal Responses ◽  
Gaba Concentration ◽  
Cell Assemblies ◽  
Gaba Transporters ◽  
Ambient Gaba ◽  
P Cells

For sensory cortices to respond reliably to feature stimuli, the balancing of neuronal excitation and inhibition is crucial. A typical example might be the balancing of phasic excitation within cell assemblies and phasic inhibition between cell assemblies. The former controls the gain of and the latter the tuning of neuronal responses. A change in ambient GABA concentration might affect the dynamic behavior of neurons in a tonic manner. For instance, an increase in ambient GABA concentration enhances the activation of extrasynaptic receptors, augments an inhibitory current, and thus inhibits neurons. When a decrease in ambient GABA concentration occurs, the tonic inhibitory current is reduced, and thus the neurons are relatively excited. We simulated a neural network model in order to examine whether and how such a tonic excitatory-inhibitory mechanism could work for sensory information processing. The network consists of cell assemblies. Each cell assembly, comprising principal cells (P), GABAergic interneurons (Ia, Ib), and glial cells (glia), responds to one particular feature stimulus. GABA transporters, embedded in glial plasma membranes, regulate ambient GABA levels. Hypothetical neuron-glia signaling via inhibitory (Ia-to-glia) and excitatory (P-to-glia) synaptic contacts was assumed. The former let transporters import (remove) GABA from the extracellular space and excited stimulus-relevant P cells. The latter let them export GABA into the extracellular space and inhibited stimulus-irrelevant P cells. The main finding was that the glial membrane transporter gave a combinatorial excitatory-inhibitory effect on P cells in a tonic manner, thereby improving the gain and tuning of neuronal responses. Interestingly, it worked cooperatively with the conventional, phasic excitatory-inhibitory mechanism. We suggest that the GABAergic gliotransmission mechanism may provide balanced intracortical excitation and inhibition so that the best perceptual performance of the cortex can be achieved.

GABA Transporter Preserving Ongoing Spontaneous Neuronal Activity at Firing Subthreshold

2009 ◽  
Vol 21 (6) ◽  
pp. 1683-1713 ◽  
Author(s):  
Osamu Hoshino
Keyword(s):  
Neuronal Activity ◽  
Extracellular Space ◽  
Transport Mechanism ◽  
Reversal Potential ◽  
Membrane Potentials ◽  
Gaba Transporter ◽  
Cell Assemblies ◽  
Time Period ◽  
Ambient Gaba ◽  
Spontaneous Neuronal Activity

There has been compelling evidence that the GABA transporter is crucial not only for removing gamma-aminobutyric acid (GABA) from but also releasing it into extracellular space, thereby clamping ambient GABA (GABA in extracellular space) at a certain level. The ambient GABA is known to activate extrasynaptic GABA receptors and provide tonic inhibitory current into neurons. We investigated how the transporter regulates the level of ambient GABA, mediates tonic neuronal inhibition, and influences ongoing spontaneous neuronal activity. A cortical neural network model is proposed in which GABA transporters on lateral (L) and feedback (F) inhibitory (GABAergic) interneurons are functionally made. Principal (P) cell assemblies participate in expressing information about elemental sensory features. At membrane potentials below the reversal potential, there is net influx of GABA, whereas at membrane potentials above the reversal potential, there is net efflux of GABA. Through this transport mechanism, ambient GABA concentration is kept within a submicromolar range during an ongoing spontaneous neuronal activity time period. Here we show that the GABA transporter on L cells regulates the overall level of ambient GABA across cell assemblies, and that on F cells it does so within individual cell assemblies. This combinatorial regulation of ambient GABA allows P cells to oscillate near firing threshold during the ongoing time period, thereby reducing their reaction time to externally applied stimuli. We suggest that the GABA transporter, with its forward and reverse transport mechanism, could regulate the ambient GABA. This transporter-mediated ambient GABA regulation may contribute to establishing an ongoing subthreshold neuronal state by which the network can respond rapidly to subsequent sensory input.

Deficient GABAergic Gliotransmission May Cause Broader Sensory Tuning in Schizophrenia

2013 ◽  
Vol 25 (12) ◽  
pp. 3235-3262 ◽  
Author(s):  
Osamu Hoshino
Keyword(s):  
Glial Cell ◽  
Glial Cells ◽  
Extracellular Space ◽  
Regulatory Mechanism ◽  
Intracortical Inhibition ◽  
Gaba Concentration ◽  
Principal Cells ◽  
Dynamic Cell ◽  
Ambient Gaba ◽  
Feature Stimulus

We examined how the depression of intracortical inhibition due to a reduction in ambient GABA concentration impairs perceptual information processing in schizophrenia. A neural network model with a gliotransmission-mediated ambient GABA regulatory mechanism was simulated. In the network, interneuron-to-glial-cell and principal-cell-to-glial-cell synaptic contacts were made. The former hyperpolarized glial cells and let their transporters import (remove) GABA from the extracellular space, thereby lowering ambient GABA concentration, reducing extrasynaptic GABAa receptor-mediated tonic inhibitory current, and thus exciting principal cells. In contrast, the latter depolarized the glial cells and let the transporters export GABA into the extracellular space, thereby elevating the ambient GABA concentration and thus inhibiting the principal cells. A reduction in ambient GABA concentration was assumed for a schizophrenia network. Multiple dynamic cell assemblies were organized as sensory feature columns. Each cell assembly responded to one specific feature stimulus. The tuning performance of the network to an applied feature stimulus was evaluated in relation to the level of ambient GABA. Transporter-deficient glial cells caused a deficit in GABAergic gliotransmission and reduced ambient GABA concentration, which markedly deteriorated the tuning performance of the network, broadening the sensory tuning. Interestingly, the GABAergic gliotransmission mechanism could regulate local ambient GABA levels: it augmented ambient GABA around stimulus-irrelevant principal cells, while reducing ambient GABA around stimulus-relevant principal cells, thereby ensuring their selective responsiveness to the applied stimulus. We suggest that a deficit in GABAergic gliotransmission may cause a reduction in ambient GABA concentration, leading to a broadening of sensory tuning in schizophrenia. The GABAergic gliotransmission mechanism proposed here may have an important role in the regulation of local ambient GABA levels, thereby improving the sensory tuning performance of the cortex.

Reduction of Trial-to-Trial Perceptual Variability by Intracortical Tonic Inhibition

2016 ◽  
Vol 28 (1) ◽  
pp. 187-215 ◽  
Author(s):  
Osamu Hoshino ◽  
Meihong Zheng ◽  
Kazuo Watanabe
Keyword(s):  
Neuronal Activity ◽  
Network Model ◽  
Dependent Manner ◽  
Gaba Concentration ◽  
Cell Assemblies ◽  
Principal Cells ◽  
Ambient Gaba ◽  
Spontaneous Neuronal Activity ◽  
Perceptual Variability ◽  
Feature Stimulus

Variability is a prominent characteristic of cognitive brain function. For instance, different trials of presentation of the same stimulus yield higher variability in its perception: subjects sometimes fail in perceiving the same stimulus. Perceptual variability could be attributable to ongoing-spontaneous fluctuation in neuronal activity prior to sensory stimulation. Simulating a cortical neural network model, we investigated the underlying neuronal mechanism of perceptual variability in relation to variability in ongoing-spontaneous neuronal activity. In the network model, populations of principal cells (cell assemblies) encode information about sensory features. Each cell assembly is sensitive to one particular feature stimulus. Transporters on GABAergic interneurons regulate ambient GABA concentration in a neuronal activity-dependent manner. Ambient GABA molecules activate extrasynaptic GABA[Formula: see text] receptors on principal cells and interneurons, and provide them with tonic inhibitory currents. We controlled the variability of ongoing-spontaneous neuronal activity by manipulating the basal level of ambient GABA and assessed the perceptual performance of the network: detection of a feature stimulus. In an erroneous response, stimulus-irrelevant but not stimulus-relevant principal cells were activated, generating trains of action potentials. Perceptual variability, reflected in error rate in detecting the same stimulus that was presented repeatedly to the network, was increased as the variability in ongoing-spontaneous membrane potential among cell assemblies increased. Frequent, transient membrane depolarization below firing threshold was the major cause of the increased neuronal variability, for which a decrease in basal ambient GABA concentration was responsible. We suggest that ambient GABA in the brain may have a role in reducing the variability in ongoing-spontaneous neuronal activity, leading to a decrease in perceptual variability and therefore to reliable sensory perception.

scholarly journals Redistribution of alpha-granules and their contents in thrombin-stimulated platelets.

1984 ◽  
Vol 98 (2) ◽  
pp. 748-760 ◽  
Author(s):  
P E Stenberg ◽  
M A Shuman ◽  
S P Levine ◽  
D F Bainton
Keyword(s):  
Plasma Membrane ◽  
Tannic Acid ◽  
Extracellular Space ◽  
Plasma Membranes ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Thin Sections ◽  
Immunocytochemical Techniques ◽  
Morphologic Changes ◽  
Stimulation Of

The redistribution of beta-thromboglobulin (beta TG), platelet Factor 4 (PF4), and fibrinogen from the alpha granules of the platelet after stimulation with thrombin was studied by morphologic and immunocytochemical techniques. The use of tannic acid stain and quick-freeze techniques revealed several thrombin-induced morphologic changes. First, the normally discoid platelet became rounder in form, with filopodia, and the granules clustered in its center. The granules then fused with one another and with elements of the surface-connected canalicular system (SCCS) to form large vacuoles in the center of the cell and near the periphery. Neither these vacuoles nor the alpha granules appeared to fuse with the plasma membrane, but the vacuoles were connected to the extracellular space by wide necks, presumably formed by enlargement of the narrow necks connecting the SCCS to the surface of the unstimulated cell. The presence of fibrinogen, beta TG, and PF4 in corresponding large intracellular vacuoles and along the platelet plasma membrane after thrombin stimulation was demonstrated by immunocytochemical techniques in saponin-permeabilized and nonpermeabilized platelets. Immunocytochemical labeling of the three proteins on frozen thin sections of thrombin-stimulated platelets confirmed these findings and showed that all three proteins reached the plasma membrane by the same pathway. We conclude that thrombin stimulation of platelets causes at least some of the fibrinogen, beta TG, and PF4 stored in their alpha granules to be redistributed to their plasma membranes by way of surface-connected vacuoles formed by fusion of the alpha granules with elements of the SCCS.

Changing the “When” and “What” of Intended Actions

2009 ◽  
Vol 102 (5) ◽  
pp. 2755-2762 ◽  
Author(s):  
Sukhvinder S. Obhi ◽  
Shannon Matkovich ◽  
Robert Chen
Keyword(s):  
Reaction Time ◽  
Simple Reaction Time ◽  
Index Finger ◽  
Sensory Information ◽  
Motor Preparation ◽  
Warning Stimulus ◽  
Inhibitory Mechanism ◽  
Preparatory Period ◽  
The Cost ◽  
Reaction Time Condition

Humans often have to modify the timing and/or type of their planned actions on the basis of new sensory information. In the present experiments, participants planned to make a right index finger keypress 3 s after a warning stimulus but on some trials were interrupted by a temporally unpredictable auditory tone prompting the same action ( experiment 1) or a different action ( experiment 2). In experiment 1, by comparing the reaction time (RT) to tones presented at different stages of the preparatory period to RT in a simple reaction time condition, we determined the cost of switching from an internally generated mode of response production to an externally triggered mode in situations requiring only a change in when an action is made (i.e., when the tone prompts the action at a different time from the intended time of action). Results showed that the cost occurred for interruption tones delivered 200 ms after a warning stimulus and remained relatively stable throughout most of the preparatory period with a reduction in the magnitude of the cost during the last 200 ms prior to the intended time of movement. In experiment 2, which included conditions requiring a change in both when and what action is produced on the tone, results show a larger cost when the switched to action is different from the action being prepared. We discuss our results in the light of neurophysiological experiments on motor preparation and suggest that intending to act is accompanied by a general inhibitory mechanism preventing premature motor output and a specific excitatory process pertaining to the intended movement. Interactions between these two mechanisms could account for our behavioral results.

scholarly journals GABA transporters regulate tonic and synaptic GABAA receptor-mediated currents in the suprachiasmatic nucleus neurons

2017 ◽  
Vol 118 (6) ◽  
pp. 3092-3106 ◽  
Author(s):  
Michael Moldavan ◽  
Olga Cravetchi ◽  
Charles N. Allen
Keyword(s):  
Circadian Clock ◽  
Suprachiasmatic Nucleus ◽  
Dependent Manner ◽  
Circadian Period ◽  
Gaba Concentration ◽  
Gaba Transporter ◽  
Concentration Dependent Manner ◽  
Gaba Transport ◽  
Gaba Transporters ◽  
Tonic Current

GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 µM each) significantly reduced the circadian period of Per1 expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAAR-mediated currents and the circadian clock in the SCN. NEW & NOTEWORTHY In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of Per1 expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABAA receptor-mediated currents and the circadian clock.

scholarly journals On gap junction structure.

1980 ◽  
Vol 86 (1) ◽  
pp. 190-198 ◽  
Author(s):  
G Zampighi ◽  
J M Corless ◽  
J D Robertson
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Rat Liver ◽  
Extracellular Space ◽  
Plasma Membranes ◽  
Negative Staining ◽  
The Other ◽  
Central Axis ◽  
Thin Sectioning ◽  
Junction Structure

We have studied the stain distribution within rat liver gap junctions for specimens prepared by thin sectioning and negative staining. Pools of stain molecules exist in two specific locations with respect to the distinctive morphological units (connexons) of the junction. One pool of stain surrounds the connexons and is restricted to the extracellular space in the gap between the adjacent plasma membranes. The other pool of stain is located along in the central axis of each connexon, measures 1-2 nm in diameter and 4-5 nm in length, and is restricted to the gap region. On rare occasions, barely discernible linear densities seem to extend from this latter pool of stain and traverse the entire width of the junction. The data indicate the existence of a hydrophilic cavity along the central axis of te connexon which, in most instances, is restricted to the gap region. However, the precise depth to which this cavity may further extend along the connexon axis is still uncertain.

Pathway of insulin in pancreatic tissue on its release by the B-cell

1993 ◽  
Vol 264 (2) ◽  
pp. G187-G194 ◽  
Author(s):  
M. Bendayan
Keyword(s):  
Plasma Membrane ◽  
B Cell ◽  
Extracellular Space ◽  
Plasma Membranes ◽  
Protein A ◽  
Intercellular Junctions ◽  
Pancreatic Tissue ◽  
Blood Capillaries ◽  
Pancreatic Cells ◽  
Subendothelial Space

Insulin was revealed in the extracellular space and blood capillaries of the rat pancreas by applying protein A-gold immunocytochemistry. On the discharge by the B-cell, insulin diffuses in the extracellular space and interacts with the plasma membrane of all pancreatic cells. For the B-cell, the interstitial microvillar plasma membrane domain was preferentially labeled compared with the flat domain. In contrast, the digitations and flat domains of the basal plasma membrane of the acinar cells were equally labeled. In the endothelium, the labeling was superior in fenestrated areas than in the high cytoplasmic ones, the fenestrae, the luminal and abluminal plasma membranes being labeled. In the cytoplasmic areas the plasmalemmal vesicles were significantly labeled; the intercellular junctions were not. These results indicate that upon binding to the membrane, the transfer of insulin across the capillaries occurs through both the fenestrations and the vesicular system. The labeling of insulin in the subendothelial space and blood capillaries decreased significantly from the insular to the peri-insular and further to the teleinsular regions, demonstrating that insulin levels, high in insular tissue, decrease very rapidly as insulin circulates through and out of the pancreas. The pancreatic cells are thus exposed to very high levels of insulin that vary according to the regions, probably contributing to the topographical partition of the acinar parenchyma into peri-insular and teleinsular tissues.

Regulation of Ambient GABA Levels by Neuron-Glia Signaling for Reliable Perception of Multisensory Events

2012 ◽  
Vol 24 (11) ◽  
pp. 2964-2993 ◽  
Author(s):  
Osamu Hoshino
Keyword(s):  
Glial Cells ◽  
Extracellular Space ◽  
Sensory Modality ◽  
Gabaergic Interneuron ◽  
Gain Function ◽  
Principal Cells ◽  
Ambient Gaba ◽  
The Cross ◽  
Multisensory Information ◽  
Stimulation Of

Activities of sensory-specific cortices are known to be suppressed when presented with a different sensory modality stimulus. This is referred to as cross-modal inhibition, for which the conventional synaptic mechanism is unlikely to work. Interestingly, the cross-modal inhibition could be eliminated when presented with multisensory stimuli arising from the same event. To elucidate the underlying neuronal mechanism of cross-modal inhibition and understand its significance for multisensory information processing, we simulated a neural network model. Principal cell to and GABAergic interneuron to glial cell projections were assumed between and within lower-order unimodal networks (X and Y), respectively. Cross-modality stimulation of Y network activated its principal cells, which then depolarized glial cells of X network. This let transporters on the glial cells export GABA molecules into the extracellular space and increased a level of ambient (extrasynaptic) GABA. The ambient GABA molecules were accepted by extrasynaptic GABAa receptors and tonically inhibited principal cells of the X network. Cross-modal inhibition took place in a nonsynaptic manner. Identical modality stimulation of X network activated its principal cells, which then activated interneurons and hyperpolarized glial cells of the X network. This let their transporters import (remove) GABA molecules from the extracellular space and reduced tonic inhibitory current in principal cells, thereby improving their gain function. Top-down signals from a higher-order multimodal network (M) contributed to elimination of the cross-modal inhibition when presented with multisensory stimuli that arose from the same event. Tuning into the multisensory event deteriorated if the cross-modal inhibitory mechanism did not work. We suggest that neuron-glia signaling may regulate local ambient GABA levels in order to coordinate cross-modal inhibition and improve neuronal gain function, thereby achieving reliable perception of multisensory events.

The Transmembrane Sodium Gradient Influences Ambient GABA Concentration by Altering the Equilibrium of GABA Transporters

2006 ◽  
Vol 96 (5) ◽  
pp. 2425-2436 ◽  
Author(s):  
Yuanming Wu ◽  
Wengang Wang ◽  
George B. Richerson
Keyword(s):  
Hippocampal Slices ◽  
Gaba Release ◽  
Synaptic Cleft ◽  
Tonic Inhibition ◽  
Multiple Sources ◽  
Sodium Removal ◽  
Gaba Transporters ◽  
Sodium Gradient ◽  
Ambient Gaba ◽  
Tonic Current

Tonic inhibition is widely believed to be caused solely by “spillover” of GABA that escapes the synaptic cleft and activates extrasynaptic GABAA receptors. However, an exclusively vesicular source is not consistent with the observation that tonic inhibition can still occur after blocking vesicular release. Here, we made patch-clamp recordings from neurons in rat hippocampal cultures and measured the tonic current that was blocked by bicuculline or gabazine. During perforated patch recordings, the tonic GABA current was decreased by the GAT1 antagonist SKF-89976a. Zero calcium solution did not change the amount of tonic current, despite a large reduction in vesicular GABA release. Perturbations that would be expected to alter the transmembrane sodium gradient influenced the tonic current. For example, in zero calcium Ringer, TTX (which can decrease cytosolic [Na+]) reduced tonic current, whereas veratridine (which can increase cytosolic [Na+]) increased tonic current. Likewise, removal of extracellular sodium led to a large increase in tonic current. The increases in tonic current induced by veratridine and sodium removal were completely blocked by SKF89976a. When these experiments were repeated in hippocampal slices, similar results were obtained except that a GAT1- and GAT3-independent nonvesicular source(s) of GABA was found to contribute to the tonic current. We conclude that multiple sources can contribute to ambient GABA, including spillover and GAT1 reversal. The source of GABA release may be conceptually less important in determining the amount of tonic inhibition than the factors that control the equilibrium of GABA transporters.

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