Model of Gamma Frequency Burst Discharge Generated by Conditional Backpropagation

2001 ◽  
Vol 86 (4) ◽  
pp. 1523-1545 ◽  
Author(s):  
Brent Doiron ◽  
André Longtin ◽  
Ray W. Turner ◽  
Leonard Maler
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Refractory Period ◽  
Core Model ◽  
Burst Discharge ◽  
The Core ◽  
Dendritic Spikes ◽  
Dendritic Spike ◽  
Frequency Burst ◽  
Spike Bursts

Pyramidal cells of the electrosensory lateral line lobe (ELL) of the weakly electric fish Apteronotus leptorhynchus have been shown to produce oscillatory burst discharge in the γ-frequency range (20–80 Hz) in response to constant depolarizing stimuli. Previous in vitro studies have shown that these bursts arise through a recurring spike backpropagation from soma to apical dendrites that is conditional on the frequency of action potential discharge (“conditional backpropagation”). Spike bursts are characterized by a progressive decrease in inter-spike intervals (ISIs), and an increase of dendritic spike duration and the amplitude of a somatic depolarizing afterpotential (DAP). The bursts are terminated when a high-frequency somatic spike doublet exceeds the dendritic spike refractory period, preventing spike backpropagation. We present a detailed multi-compartmental model of an ELL basilar pyramidal cell to simulate somatic and dendritic spike discharge and test the conditions necessary to produce a burst output. The model ionic channels are described by modified Hodgkin-Huxley equations and distributed over both soma and dendrites under the constraint of available immunocytochemical and electrophysiological data. The currents modeled are somatic and dendritic sodium and potassium involved in action potential generation, somatic and proximal apical dendritic persistent sodium, and KV3.3 and fast transient A-like potassium channels distributed over the entire model cell. The core model produces realistic somatic and dendritic spikes, differential spike refractory periods, and a somatic DAP. However, the core model does not produce oscillatory spike bursts with constant depolarizing stimuli. We find that a cumulative inactivation of potassium channels underlying dendritic spike repolarization is a necessary condition for the model to produce a sustained γ-frequency burst pattern matching experimental results. This cumulative inactivation accounts for a frequency-dependent broadening of dendritic spikes and results in a conditional failure of backpropagation when the intraburst ISI exceeds dendritic spike refractory period, terminating the burst. These findings implicate ion channels involved in repolarizing dendritic spikes as being central to the process of conditional backpropagation and oscillatory burst discharge in this principal sensory output neuron of the ELL.

scholarly journals Persistent Na+ Current Modifies Burst Discharge By Regulating Conditional Backpropagation of Dendritic Spikes

2003 ◽  
Vol 89 (1) ◽  
pp. 324-337 ◽  
Author(s):  
Brent Doiron ◽  
Liza Noonan ◽  
Neal Lemon ◽  
Ray W. Turner
Keyword(s):  
Sodium Current ◽  
Pyramidal Cells ◽  
Weakly Electric Fish ◽  
Burst Frequency ◽  
Burst Discharge ◽  
Dendritic Spikes ◽  
Dendritic Spike ◽  
Time Required ◽  
Weakly Electric ◽  
Spike Bursts

The estimation and detection of stimuli by sensory neurons is affected by factors that govern a transition from tonic to burst mode and the frequency chracteristics of burst output. Pyramidal cells in the electrosensory lobe of weakly electric fish generate spike bursts for the purpose of stimulus detection. Spike bursts are generated during repetitive discharge when a frequency-dependent broadening of dendritic spikes increases current flow from dendrite to soma to potentiate a somatic depolarizing afterpotential (DAP). The DAP eventually triggers a somatic spike doublet with an interspike interval that falls inside the dendritic refractory period, blocking spike backpropagiation and the DAP. Repetition of this process gives rise to a rhythmic dendritic spike failure, termed conditional backpropagation, that converts cell output from tonic to burst discharge. Through in vitrorecordings and compartmental modeling we show that burst frequency is regulated by the rate of DAP potentiation during a burst, which determines the time required to discharge the spike doublet that blocks backpropagation. DAP potentiation is maginfied through a postitve feedback process when an increase in dendritic spike duration activates persistent sodium current ( I NaP). I NaP further promotes a slow depolarization that induces a shift from tonic to burst discharge over time. The results are consistent with a dynamical systems analysis that shows that the threshold separating tonic and burst discharge can be represented as a saddle-node bifurcation. The interaction between dendritic K+ current and I NaP provides a physiological explanation for a variable time scale of bursting dynamics characteristic of such a bifurcation.

Frequency- and voltage-dependent effects of disopyramide in canine Purkinje fibers

1989 ◽  
Vol 67 (7) ◽  
pp. 710-721 ◽  
Author(s):  
Matthew A. Flemming ◽  
Betty I. Sasyniuk
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Sodium Channel ◽  
Action Potential Duration ◽  
Refractory Period ◽  
Drug Effect ◽  
Effective Refractory Period ◽  
Slow Inactivation ◽  
Purkinje Fibers ◽  
Rate Dependent

The voltage- and frequency-dependent blocking actions of disopyramide were assessed in canine Purkinje fibers within the framework of concentrations, membrane potentials, and heart rates which have relevance to the therapeutic actions of this drug. [Formula: see text] was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of [Formula: see text] depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on [Formula: see text]. A concentration-dependent increase in tonic block was also observed. Despite significant increases in tonic block at more depolarized potentials, rate-dependent block increased only marginally with membrane potential over the range of potentials in which propagated action potentials occur. Increases in extracellular potassium concentration accentuated drug effect on [Formula: see text] but attenuated drug effect on action potential duration. Recovery from rate-dependent block followed two exponential processes with time constants of 689 ± 535 ms and 15.7 ± 2.7 s. The latter component represents dissociation of drug from its binding site and the former probably represents recovery from slow inactivation. A concentration-dependent increase in the amplitude of the first component suggested that disopyramide may promote slow inactivation. There was less than 5% recovery from block during intervals equivalent to clinical diastole. Thus, depression of beats of all degrees of prematurity was similar to that of basic drive beats. Prolongation of action potential duration by therapeutic concentrations of drug following a long quiescent interval was minimal. However, profound lengthening of action potential duration occurred following washout of drug effect at a time when [Formula: see text] depression had reverted to normal, suggesting that binding of disopyramide to potassium channels may not be readily reversed. Variable effects on action potential duration may thus be attributed to a block of the window current flowing during the action potential being partially or over balanced by block of potassium channels. Purkinje fiber refractoriness was prolonged in a frequency-dependent manner. Disopyramide did not significantly alter the effective refractory period of basic beats but did increase the effective refractory period of sequential tightly coupled extra stimuli. The results can account for the antiarrhythmic actions of disopyramide during a rapid tachycardia and prevention of its initiation by programmed electrical stimulation.Key words: action potential duration, effective refractory period, upstroke velocity, conduction, rate of sodium channel unblocking.

scholarly journals Conditional Spike Backpropagation Generates Burst Discharge in a Sensory Neuron

2000 ◽  
Vol 84 (3) ◽  
pp. 1519-1530 ◽  
Author(s):  
N. Lemon ◽  
R. W. Turner
Keyword(s):  
Refractory Period ◽  
Interspike Interval ◽  
Pyramidal Cells ◽  
Weakly Electric Fish ◽  
Interspike Intervals ◽  
Frequency Dependent ◽  
Spike Discharge ◽  
Burst Discharge ◽  
Dendritic Spike

Backpropagating dendritic Na+spikes generate a depolarizing afterpotential (DAP) at the soma of pyramidal cells in the electrosensory lateral line lobe (ELL) of weakly electric fish. Repetitive spike discharge is associated with a progressive depolarizing shift in somatic spike afterpotentials that eventually triggers a high-frequency spike doublet and subsequent burst afterhyperpolarization (bAHP). The rhythmic generation of a spike doublet and bAHP groups spike discharge into an oscillatory burst pattern. This study examined the soma-dendritic mechanisms controlling the depolarizing shift in somatic spike afterpotentials, and the mechanism by which spike doublets terminate spike discharge. Intracellular recordings were obtained from ELL pyramidal somata and apical dendrites in an in vitro slice preparation. The pattern of spike discharge was equivalent in somatic and dendritic regions, reflecting the backpropagation of spikes from soma to dendrites. There was a clear frequency-dependent threshold in the transition from tonic to burst discharge, with bursts initiated when interspike intervals fell between ∼3–7 ms. Removal of all backpropagating spikes by dendritic TTX ejection revealed that the isolated somatic AHPs were entirely stable at the interspike intervals that generated burst discharge. As such, the depolarizing membrane potential shift during repetitive discharge could be attributed to a potentiation of DAP amplitude. Potentiation of the DAP was due to a frequency-dependent broadening and temporal summation of backpropagating dendritic Na+ spikes. Spike doublets were generated with an interspike interval close to, but not within, the somatic spike refractory period. In contrast, the interspike interval of spike doublets always fell within the longer dendritic refractory period, preventing backpropagation of the second spike of the doublet. The dendritic depolarization was thus abruptly removed from one spike to the next, allowing the burst to terminate when the bAHP hyperpolarized the membrane. The transition from tonic to burst discharge was dependent on the number and frequency of spikes invoking dendritic spike summation, indicating that burst threshold depends on the immediate history of cell discharge. Spike frequency thus represents an important condition that determines the success of dendritic spike invasion, establishing an intrinsic mechanism by which backpropagating spikes can be used to generate a rhythmic burst output.

Scales in K(ℝ) at the end of a weak gap

2008 ◽  
Vol 73 (2) ◽  
pp. 369-390 ◽  
Author(s):  
J. R. Steel
Keyword(s):  
Induction Hypothesis ◽  
The Other ◽  
Core Model ◽  
The Core ◽  
Woodin Cardinals ◽  
Other Hand

In this note we shall proveTheorem 0.1. Letbe a countably ω-iterable-mouse which satisfies AD, and [α, β] a weak gap of. Supposeis captured by mice with iteration strategies in ∣α. Let n be least such that ; then we have that believes that has the Scale Property.This complements the work of [5] on the construction of scales of minimal complexity on sets of reals in K(ℝ). Theorem 0.1 was proved there under the stronger hypothesis that all sets definable over are determined, although without the capturing hypothesis. (See [5, Theorem 4.14].) Unfortunately, this is more determinacy than would be available as an induction hypothesis in a core model induction. The capturing hypothesis, on the other hand, is available in such a situation. Since core model inductions are one of the principal applications of the construction of optimal scales, it is important to prove 0.1 as stated.Our proof will incorporate a number of ideas due to Woodin which figure prominently in the weak gap case of the core model induction. It relies also on the connection between scales and iteration strategies with the Dodd-Jensen property first discovered in [3]. Let be the pointclass at the beginning of the weak gap referred to in 0.1. In section 1, we use Woodin's ideas to construct a Γ-full a mouse having ω Woodin cardinals cofinal in its ordinals, together with an iteration strategy Σ which condenses well in the sense of [4, Def. 1.13]. In section 2, we construct the desired scale from and Σ.

Study of the Characteristics of the Pulmonary Vein and Superior Vena Cava of Rabbits

2021 ◽  
Vol 11 (1) ◽  
pp. 112-122
Author(s):  
Pan Wang ◽  
Xin-Chun Yang ◽  
Xiu-Lan Liu ◽  
Rong-Feng Bao ◽  
Huai-Yu Ding ◽  
...  
Keyword(s):  
Action Potential ◽  
Pulmonary Vein ◽  
Refractory Period ◽  
Potassium Current ◽  
Superior Vena ◽  
Vena Cava ◽  
Current Intensity ◽  
Left And Right ◽  
The Difference ◽  
Right Atria

Background: This study aims to (1) investigate the characteristics of the action potential and triggering activity of cardiomyocytes in the pulmonary vein (PV) and superior vena cava (SVC) of rabbits and (2) study the features of cation currents in cardiomyocytes in rabbit PV and SVC-inward rectifier potassium current (IK1), transient outward potassium current (Ito), and non-selective cation currents (INSCC). Methods: The standard glass microelectrode and whole-cell patch-clamp techniques were used to record the action potential and various currents in the above cells. Results: (1) Cardiomyocytes in either PV or SVC had longer action potential durations than in the adjacent atrium, and spontaneous early after depolarization (EAD) could occur in both PV and SVC under normal physiological conditions. (2) The action potential in PV cardiomyocytes had a relative refractory period but did not have an absolute refractory period, and this characteristic enabled a premature beat that triggered a second plateau response, which led to EAD. (3) INSCC was found for the first time in the PV, SVC, and atria. (4) The current intensity of IK1, Ito, and INSCC was significantly lower in the PV and SVC than in the left and right atria, and the difference in the current intensity in INSCC could influence the action potential. Conclusions: PV and SVC can both initiate and maintain AF, but PV is the primary ectopic foci in initiating AF. The present study found that the second plateau response was easily induced in cardiomyocytes in PA shortly after depolarization. This was a specific characteristic of the action potential of PV. In addition, we preliminarily analyzed the differences in the main outward currents and noted a voltage-dependent INSCC in both PV and SVC rabbits’ cardiomyocytes. Furthermore, the current intensities of IK1, Ito, and INSCC were significantly lower in the PV and SVC than in the left and right atria, and the difference in the current intensity of INSCC influenced the action potential. The different permeability of INSCC for cations at different phases may play a role in inducing EAD.

Molecular physiology of cardiac potassium channels

1996 ◽  
Vol 76 (1) ◽  
pp. 49-67 ◽  
Author(s):  
K. K. Deal ◽  
S. K. England ◽  
M. M. Tamkun
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Single Channel ◽  
Resting Membrane Potential ◽  
Molecular Physiology ◽  
K Channels ◽  
Relative Contribution ◽  
Outward Currents ◽  
Important Challenge ◽  
Heterologous Expression Systems

The cardiac action potential results from the complex, but precisely regulated, movement of ions across the sarcolemmal membrane. Potassium channels represent the most diverse class of ion channels in heart and are the targets of several antiarrhythmic drugs. Potassium currents in the myocardium can be classified into one of two general categories: 1) inward rectifying currents such as IK1, IKACh, and IKATP; and 2) primarily voltage-gated currents such as IKs, IKr, IKp, IKur, and Ito. The inward rectifier currents regulate the resting membrane potential, whereas the voltage-activated currents control action potential duration. The presence of these multiple, often overlapping, outward currents in native cardiac myocytes has complicated the study of individual K+ channels; however, the application of molecular cloning technology to these cardiovascular K+ channels has identified the primary structure of these proteins, and heterologous expression systems have allowed a detailed analysis of the function and pharmacology of a single channel type. This review addresses the progress made toward understanding the complex molecular physiology of K+ channels in mammalian myocardium. An important challenge for the future is to determine the relative contribution of each of these cloned channels to cardiac function.

scholarly journals Ceramide modulates HERG potassium channel gating by translocation into lipid rafts

2010 ◽  
Vol 299 (1) ◽  
pp. C74-C86 ◽  
Author(s):  
Sindura B. Ganapathi ◽  
Todd E. Fox ◽  
Mark Kester ◽  
Keith S. Elmslie
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Lipid Rafts ◽  
Negative Impact ◽  
Cardiac Action Potential ◽  
Cholesterol Depletion ◽  
Cardiac Action ◽  
Herg Channels ◽  
The Impact ◽  
Action Potential Repolarization

Human ether-à-go-go-related gene (HERG) potassium channels play an important role in cardiac action potential repolarization, and HERG dysfunction can cause cardiac arrhythmias. However, recent evidence suggests a role for HERG in the proliferation and progression of multiple types of cancers, making it an attractive target for cancer therapy. Ceramide is an important second messenger of the sphingolipid family, which due to its proapoptotic properties has shown promising results in animal models as an anticancer agent . Yet the acute effects of ceramide on HERG potassium channels are not known. In the present study we examined the effects of cell-permeable C6-ceramide on HERG potassium channels stably expressed in HEK-293 cells. C6-ceramide (10 μM) reversibly inhibited HERG channel current (IHERG) by 36 ± 5%. Kinetically, ceramide induced a significant hyperpolarizing shift in the current-voltage relationship (Δ V1/2 = −8 ± 0.5 mV) and increased the deactivation rate (43 ± 3% for τfast and 51 ± 3% for τslow). Mechanistically, ceramide recruited HERG channels within caveolin-enriched lipid rafts. Cholesterol depletion and repletion experiments and mathematical modeling studies confirmed that inhibition and gating effects are mediated by separate mechanisms. The ceramide-induced hyperpolarizing gating shift (raft mediated) could offset the impact of inhibition (raft independent) during cardiac action potential repolarization, so together they may nullify any negative impact on cardiac rhythm. Our results provide new insights into the effects of C6-ceramide on HERG channels and suggest that C6-ceramide can be a promising therapeutic for cancers that overexpress HERG.

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