scholarly journals GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons

2019 ◽  
Author(s):  
Alexander Bryson ◽  
Robert Hatch ◽  
Bas-Jan Zandt ◽  
Christian Rossert ◽  
Samuel Berkovic ◽  
...  
Keyword(s):  
Action Potential ◽  
Computational Models ◽  
Potassium Currents ◽  
Tonic Inhibition ◽  
Network Activity ◽  
Neuron Models ◽  
Electrophysiological Properties ◽  
Cortical Interneurons ◽  
Voltage Dependent ◽  
Tonic Current

ABSTRACTThe binding of GABA to extra-synaptic GABAAreceptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present at low levels throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes through variation in chloride gradient. Here, we introduce a distinct mechanism through which extracellular GABA can differentially modulate the excitability of neuron subtypes through variation in neuronal electrophysiological properties. Using biophysically-detailed computational models, we found that tonic inhibition enhanced the responsiveness (or gain) of models with electrophysiological features typically observed in somatostatin (Sst) interneurons and reduced gain in models with features typical for parvalbumin (Pv) interneurons. These predictions were experimentally verified using patch-clamp recordings. Further analysis revealed that differential gain modulation is also dependent upon the extent of outward rectification of the GABAAreceptor-mediated tonic current. Our detailed neuron models demonstrate two subcellular consequences of tonic inhibition. First, tonic inhibition enhances somatic action potential repolarisation by increasing current flow into the dendritic compartment. This enhanced repolarisation then reduces voltage-dependent potassium currents at the soma during the afterhyperpolarisation. Finally, we show that reductions of potassium current selectively increase gain within neurons exhibiting action potential dynamics typical for Sst interneurons. Potassium currents in Pv-type interneurons are not sensitive to this mechanism as they deactivate rapidly and are unavailable for further modulation. These findings introduce a neuromodulatory paradigm in which GABA can induce a state of differential interneuron excitability through differences in intrinsic electrophysiological properties.

scholarly journals GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons

2020 ◽  
Vol 117 (6) ◽  
pp. 3192-3202 ◽  
Author(s):  
Alexander Bryson ◽  
Robert John Hatch ◽  
Bas-Jan Zandt ◽  
Christian Rossert ◽  
Samuel F. Berkovic ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
In Silico ◽  
In Silico Analysis ◽  
Tonic Inhibition ◽  
Network Activity ◽  
Gain Modulation ◽  
Neuron Models ◽  
Electrophysiological Properties ◽  
Cortical Interneurons

The binding of GABA (γ-aminobutyric acid) to extrasynaptic GABAA receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes according to variation in chloride gradient. Here, using biophysically detailed neuron models, we predict that tonic inhibition can differentially modulate the excitability of neuron subtypes according to variation in electrophysiological properties. Surprisingly, tonic inhibition increased the responsiveness (or gain) in models with features typical for somatostatin interneurons but decreased gain in models with features typical for parvalbumin interneurons. Patch-clamp recordings from cortical interneurons supported these predictions, and further in silico analysis was then performed to seek a putative mechanism underlying gain modulation. We found that gain modulation in models was dependent upon the magnitude of tonic current generated at depolarized membrane potential—a property associated with outward rectifying GABAA receptors. Furthermore, tonic inhibition produced two biophysical changes in models of relevance to neuronal excitability: 1) enhanced action potential repolarization via increased current flow into the dendritic compartment, and 2) reduced activation of voltage-dependent potassium channels. Finally, we show theoretically that reduced potassium channel activation selectively increases gain in models possessing action potential dynamics typical for somatostatin interneurons. Potassium channels in parvalbumin-type models deactivate rapidly and are unavailable for further modulation. These findings show that GABA can differentially modulate interneuron excitability and suggest a mechanism through which this occurs in silico via differences of intrinsic electrophysiological properties.

scholarly journals Rapid regulation of tonic GABA currents in cultured rat hippocampal neurons

2013 ◽  
Vol 109 (3) ◽  
pp. 803-812 ◽  
Author(s):  
Christopher B. Ransom ◽  
Wucheng Tao ◽  
Yuanming Wu ◽  
William J. Spain ◽  
George B. Richerson
Keyword(s):  
Hippocampal Neurons ◽  
Brain Slices ◽  
Reversal Potential ◽  
Gaba Release ◽  
Tonic Inhibition ◽  
Concanamycin A ◽  
Voltage Dependent ◽  
Tonic Current ◽  
Induced Changes ◽  
Time Frames

Subacute and chronic changes in tonic GABAergic inhibition occur in human and experimental epilepsy. Less is known about how tonic inhibition is modulated over shorter time frames (seconds). We measured endogenous tonic GABA currents from cultured rat hippocampal neurons to evaluate how they are affected by 1) transient increases in extracellular GABA concentration ([GABA]), 2) transient postsynaptic depolarization, and 3) depolarization of presynaptic cells. Transient increases in [GABA] (1 μM) reduced tonic currents; this reduction resulted from GABA-induced shifts in the reversal potential for GABA currents ( EGABA). Transient depolarization of postsynaptic neurons reversed the effects of exogenous GABA and potentiated tonic currents. The voltage-dependent potentiation of tonic GABA currents was independent of EGABA shifts and represented postdepolarization potentiation (PDP), an intrinsic GABAA receptor property (Ransom CB, Wu Y, Richerson GB. J Neurosci 30: 7672–7684, 2010). Inhibition of vesicular GABA release with concanamycin A (ConA) did not affect tonic currents. In ConA-treated cells, transient application of 12 mM K+ to depolarize presynaptic neurons and glia produced a persistent increase in tonic current amplitude. The K+-induced increase in tonic current was reversibly inhibited by SKF89976a (40 μM), indicating that this was caused by nonvesicular GABA release from GABA transporter type 1 (GAT1). Nonvesicular GABA release due to GAT1 reversal also occurred in acute hippocampal brain slices. Our results indicate that tonic GABA currents are rapidly regulated by GABA-induced changes in intracellular Cl− concentration, PDP of extrasynaptic GABAA receptors, and nonvesicular GABA release. These mechanisms may influence tonic inhibition during seizures when neurons are robustly depolarized and extracellular GABA and K+ concentrations are elevated.

scholarly journals Effects of Divalent Cations on Outward Potassium Currents in Leech Retzius Nerve Cells

2016 ◽  
Vol 17 (4) ◽  
pp. 309-314
Author(s):  
Zorica Jovanovic ◽  
Olgica Mihaljevic ◽  
Irena Kostic
Keyword(s):  
Action Potential ◽  
Neuronal Excitability ◽  
Divalent Cations ◽  
Extracellular Fluid ◽  
Outward Current ◽  
Potassium Currents ◽  
Nerve Cells ◽  
Outward Currents ◽  
Voltage Dependent ◽  
Retzius Cells

Abstract The present study examines the effects of divalent metals, cadmium (Cd2+) and manganese (Mn2+), on the outward potassium currents of Retzius cells in the hirudinid leeches Haemopis sanguisuga using conventional two-microelectrode voltageclamp techniques. The outward potassium current is activated by depolarization and plays an important role in determining both the neuronal excitability and action potential duration. A strong inhibition of the fast current and a clear reduction in the late currents of the outward current with 1 mM Cd2+ were obtained, which indicated that both components are sensitive to this metal. Complete blockage of the fast and partial reduction of the slow outward currents was observed after adding 1 mM Mn2+ to the extracellular fluid. These data show that the outward K+ current in leech Retzius nerve cells comprises at least two components: a voltage-dependent K+ current and a Ca2+- activated K+ current. These observations also indicate that Cd2+ is more eff ective than Mn2+ in blocking ion fl ow through these channels and that suppressing Ca2+-activated K+ outward currents can prolong the action potential in nerve cells.

Three Types of Depolarization-Activated Potassium Currents in Acutely Isolated Mouse Vestibular Neurons

2001 ◽  
Vol 85 (3) ◽  
pp. 1017-1026 ◽  
Author(s):  
C. Chabbert ◽  
J. M. Chambard ◽  
A. Sans ◽  
G. Desmadryl
Keyword(s):  
Potassium Currents ◽  
Primary Neurons ◽  
Patch Clamp Technique ◽  
Electrophysiological Properties ◽  
The Third ◽  
Recovery From Inactivation ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Fast Activation ◽  
20 Nm

The nature and electrophysiological properties of Ca2+-independent depolarization-activated potassium currents were investigated in vestibular primary neurons acutely isolated from postnatal mice using the whole cell configuration of the patch-clamp technique. Three types of currents were identified. The first current, sensitive to TEA ( I TEA) and insensitive to 4-aminopyridine (4-AP), activated at −40 mV and exhibited slow activation ( τ ac, 38.4 ± 7.8 ms at −30 mV, mean ± SD). I TEA had a half activation potential [ V ac(1/2)] of −14.5 ± 2.6 mV and was inactivated by up to 84.5 ± 5.7% by 10-s conditioning prepulses with a half inactivation potential [ V inac(1/2)] of −62.4 ± 0.2 mV. The second current, sensitive to 4-AP (maximum block around 0.5 mM) and to α-dendrotoxin ( I DTX) appeared at −60 mV. Complete block of I DTX was achieved using either 20 nM α-DTX or 50 nM margatoxin. This current activated 10 times faster than I TEA( τ ac, 3.5 ± 0.8 ms at −50 mV) with V ac(1/2) of −51.2 ± 0.6 mV, and inactivated only slightly compared with I TEA (maximum inactivation, 19.7 ± 3.2%). The third current, also sensitive to 4-AP (maximum block at 2 mM), was selectively blocked by application of blood depressing substance (BDS-I; maximum block at 250 nM). The BDS-I–sensitive current ( I BDS-I) activated around −60 mV. It displayed fast activation ( τ ac, 2.3 ± 0.4 ms at −50 mV) and fast and complete voltage-dependent inactivation. I BDS-I had a V ac(1/2) of −31.3 ± 0.4 mV and V inac(1/2) of −65.8 ± 0.3 mV. It displayed faster time-dependent inactivation and recovery from inactivation than I TEA. The three types of current were found in all the neurons investigated. Although I TEA was the major current, the proportion of I DTX and I BDS-I varied considerably between neurons. The ratio of the density of I BDS-I to that of I DTX ranged from 0.02 to 2.90 without correlation with the cell capacitances. In conclusion, vestibular primary neurons differ by the proportion rather than the type of the depolarization-activated potassium currents they express.

Electrophysiological properties of guinea pig trigeminal motoneurons recorded in vitro

1994 ◽  
Vol 71 (1) ◽  
pp. 129-145 ◽  
Author(s):  
S. H. Chandler ◽  
C. F. Hsaio ◽  
T. Inoue ◽  
L. J. Goldberg
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Inward Rectification ◽  
Electrophysiological Properties ◽  
Calcium Dependent ◽  
Current Pulses ◽  
Bath Application ◽  
Voltage Dependent ◽  
Trigeminal Motoneurons ◽  
Frequency Current

1. Intracellular recording and stimulation were made from guinea pig trigeminal motoneurons (TMNs) in brain stem slices. Electrophysiological properties were examined and the underlying currents responsible for motoneuron excitability were investigated by the use of current clamp and single electrode voltage clamp (SEVC) techniques. 2. The voltage responses to subthreshold hyperpolarizing or depolarizing current pulses showed voltage- and time-dependent inward rectification. SEVC analysis demonstrated that the hyperpolarizing inward rectification resulted from the development of a slowly occurring voltage-dependent inward current activated at hyperpolarized membrane potentials. This current persisted in solutions containing low Ca2+/Mn2+, tetraethylammonium (TEA), and Ba2+, whereas it was reduced by 1–3 mM cesium. The depolarizing inward rectification was mediated by a persistent sodium current (INa-P) that was completely abolished by bath application of tetrodotoxin (TTX). 3. Action potential characteristics were studied by intracellular stimulation with brief current pulses (< 3 ms) in combination with ionic substitutions or application of specific ionic conductance blocking agents. Bath application of TTX abolished the action potential, whereas 1–10 mM TEA or 0.5–2 mM 4-aminopyridine (4-AP) increased, significantly, the spike duration, suggesting participation of the delayed rectifier and A-current type conductances in spike repolarization. SEVC analysis revealed a TEA-sensitive sustained outward current and a fast, voltage-dependent, transient current with properties consistent with their roles in spike repolarization. 4. TMN afterhyperpolarizing potentials (AHPs) that followed a single spike consisted of fast and slow components usually separated by a depolarizing hump [afterdepolarization (ADP)]. The fast component was abolished by TEA or 4-AP but not by Mn2+, Co2+, or the bee venom apamin. In contrast, the slow AHP was readily reduced by Mn2+, Co2+, or apamin, suggesting participation of an apamin-sensitive, calcium-dependent K+ conductance in the production of the slow AHP. SEVC analysis and ionic substitutions demonstrated a slowly activating and deactivating calcium-dependent K+ current with properties that could account for the slow AHP observed in these neurons. 5. Repetitive discharge was examined with long depolarizing current pulses (1 s) and analysis of frequency-current plots. When evoked from resting potential (about -55 mV), spike onset from rheobase occurred rapidly and was maintained throughout the current pulse. At higher current intensities, early and late adaptations in spike discharge were observed. Frequency-current plots exhibited a bilinear relationship for the first interspike interval (ISI) in approximately 50% of the neurons tested and in most neurons tested during steady-state discharge (SS).(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals A model of on/off transitions in neurons of the deep cerebellar nuclei: deciphering the underlying ionic mechanisms

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hugues Berry ◽  
Stéphane Genet
Keyword(s):  
Cerebellar Nuclei ◽  
Biophysical Model ◽  
High Threshold ◽  
Deep Cerebellar Nuclei ◽  
Functional Link ◽  
Electrophysiological Properties ◽  
Voltage Dependent ◽  
Ionic Mechanisms ◽  
The Central Nervous System ◽  
Overall Functioning

AbstractThe neurons of the deep cerebellar nuclei (DCNn) represent the main functional link between the cerebellar cortex and the rest of the central nervous system. Therefore, understanding the electrophysiological properties of DCNn is of fundamental importance to understand the overall functioning of the cerebellum. Experimental data suggest that DCNn can reversibly switch between two states: the firing of spikes (F state) and a stable depolarized state (SD state). We introduce a new biophysical model of the DCNn membrane electro-responsiveness to investigate how the interplay between the documented conductances identified in DCNn give rise to these states. In the model, the F state emerges as an isola of limit cycles, i.e. a closed loop of periodic solutions disconnected from the branch of SD fixed points. This bifurcation structure endows the model with the ability to reproduce the $\text{F}\to \text{SD}$ F → SD transition triggered by hyperpolarizing current pulses. The model also reproduces the $\text{F}\to \text{SD}$ F → SD transition induced by blocking Ca currents and ascribes this transition to the blocking of the high-threshold Ca current. The model suggests that intracellular current injections can trigger fully reversible $\text{F}\leftrightarrow \text{SD}$ F ↔ SD transitions. Investigation of low-dimension reduced models suggests that the voltage-dependent Na current is prominent for these dynamical features. Finally, simulations of the model suggest that physiological synaptic inputs may trigger $\text{F}\leftrightarrow \text{SD}$ F ↔ SD transitions. These transitions could explain the puzzling observation of positively correlated activities of connected Purkinje cells and DCNn despite the former inhibit the latter.

scholarly journals Segmental differences in firing properties and potassium currents in Drosophila larval motoneurons

2012 ◽  
Vol 107 (5) ◽  
pp. 1356-1365 ◽  
Author(s):  
Subhashini Srinivasan ◽  
Kimberley Lance ◽  
Richard B. Levine
Keyword(s):  
Patch Clamp ◽  
Abdominal Segment ◽  
Body Wall ◽  
Potassium Currents ◽  
Whole Cell Patch Clamp ◽  
Voltage Dependent ◽  
Body Wall Muscles ◽  
Motoneuron Activity ◽  
Firing Properties ◽  
Thoracic And Abdominal

Potassium currents play key roles in regulating motoneuron activity, including functional specializations that are important for locomotion. The thoracic and abdominal segments in the Drosophila larval ganglion have repeated arrays of motoneurons that innervate body-wall muscles used for peristaltic movements during crawling. Although abdominal motoneurons and their muscle targets have been studied in detail, owing, in part, to their involvement in locomotion, little is known about the cellular properties of motoneurons in thoracic segments. The goal of this study was to compare firing properties among thoracic motoneurons and the potassium currents that influence them. Whole-cell, patch-clamp recordings performed from motoneurons in two thoracic and one abdominal segment revealed both transient and sustained voltage-activated K+ currents, each with Ca++-sensitive and Ca++-insensitive [A-type, voltage-dependent transient K+ current (IAv)] components. Segmental differences in the expression of voltage-activated K+ currents were observed. In addition, we demonstrate that Shal contributes to IAv currents in the motoneurons of the first thoracic segment.

Rate-dependent shortening of action potential duration increases ventricular vulnerability in failing rabbit heart

2011 ◽  
Vol 300 (2) ◽  
pp. H565-H573 ◽  
Author(s):  
Masahide Harada ◽  
Yukiomi Tsuji ◽  
Yuko S. Ishiguro ◽  
Hiroki Takanari ◽  
Yusuke Okuno ◽  
...  
Keyword(s):  
Action Potential ◽  
High Frequency ◽  
Rabbit Heart ◽  
Left Ventricular ◽  
High Frequency Stimulation ◽  
Electrophysiological Properties ◽  
Rate Dependent ◽  
Frequency Stimulation ◽  
And Control

Congestive heart failure (CHF) predisposes to ventricular fibrillation (VF) in association with electrical remodeling of the ventricle. However, much remains unknown about the rate-dependent electrophysiological properties in a failing heart. Action potential properties in the left ventricular subepicardial muscles during dynamic pacing were examined with optical mapping in pacing-induced CHF ( n = 18) and control ( n = 17) rabbit hearts perfused in vitro. Action potential durations (APDs) in CHF were significantly longer than those observed for controls at basic cycle lengths (BCLs) >1,000 ms but significantly shorter at BCLs <400 ms. Spatial APD dispersions were significantly increased in CHF versus control (by 17–81%), and conduction velocity was significantly decreased in CHF (by 6–20%). In both groups, high-frequency stimulation (BCLs <150 ms) always caused spatial APD alternans; spatially concordant alternans and spatially discordant alternans (SDA) were induced at 60% and 40% in control, respectively, whereas 18% and 82% in CHF. SDA in CHF caused wavebreaks followed by reentrant excitations, giving rise to VF. Incidence of ventricular tachycardia/VFs elicited by high-frequency dynamic pacing (BCLs <150 ms) was significantly higher in CHF versus control (93% vs. 20%). In CHF, left ventricular subepicardial muscles show significant APD shortenings at short BCLs favoring reentry formations following wavebreaks in association with SDA. High-frequency excitation itself may increase the vulnerability to VF in CHF.

A background sodium conductance is necessary for spontaneous depolarizations in rat pituitary cell line GH3

1994 ◽  
Vol 266 (3) ◽  
pp. C709-C719 ◽  
Author(s):  
S. M. Simasko
Keyword(s):  
Cell Line ◽  
Calcium Current ◽  
Membrane Conductance ◽  
Potassium Currents ◽  
Pituitary Cell ◽  
Calcium Currents ◽  
Gh3 Cells ◽  
Sodium Conductance ◽  
Rat Pituitary ◽  
Voltage Dependent

The role of Na+ in the expression of membrane potential activity in the clonal rat pituitary cell line GH3 was investigated using the perforated patch variation of patch-clamp electrophysiological techniques. It was found that replacing bath Na+ with choline, tris(hydroxymethyl)aminomethane (Tris), or N-methyl-D-glucamine (NMG) caused the cells to hyperpolarize 20-30 mV. Tetrodotoxin had no effect. The effects of the Na+ substitutes could not be explained by effects on potassium or calcium currents. Although all three Na+ substitutes suppressed voltage-dependent calcium current by 10-20%, block of voltage-dependent calcium current by nifedipine or Co2+ did not result in hyperpolarization of the cells. There was no effect of the Na+ substitutes on voltage-dependent potassium currents. In contrast, all three Na+ substitutes influenced calcium-activated potassium currents [IK(Ca)], but only at depolarized potentials. Choline consistently suppressed IK(Ca), whereas Tris and NMG either had no effect or slightly increased IK(Ca). These effects on IK(Ca) also cannot explain the hyperpolarization induced by removing bath Na+. Choline always hyperpolarized cells yet suppressed IK(Ca). Furthermore, removing bath Na+ caused an increase in cell input resistance, an observation consistent with the loss of a membrane conductance as the basis of the hyperpolarization. Direct measurement of background currents revealed a 12-pA inward current at -84 mV that was lost upon removing bath Na+. These results suggest that this background sodium conductance provides the depolarizing drive for GH3 cells to reach the threshold for firing calcium-dependent action potentials.

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