Resilient RTN Fast Spiking in Kv3.1 Null Mice Suggests Redundancy in the Action Potential Repolarization Mechanism

2002 ◽  
Vol 87 (3) ◽  
pp. 1303-1310 ◽  
Author(s):  
Darrell M. Porcello ◽  
Chi Shun Ho ◽  
Rolf H. Joho ◽  
John R. Huguenard
Keyword(s):  
Action Potential ◽  
High Frequency ◽  
Action Potentials ◽  
Brain Slices ◽  
Firing Frequency ◽  
Wild Type ◽  
Genetic Redundancy ◽  
Fast Spiking ◽  
Deficient Mice ◽  
Action Potential Repolarization

Fast spiking (FS), GABAergic neurons of the reticular thalamic nucleus (RTN) are capable of firing high-frequency trains of brief action potentials, with little adaptation. Studies in recombinant systems have shown that high-voltage-activated K+ channels containing the Kv3.1 and/or Kv3.2 subunits display biophysical properties that may contribute to the FS phenotype. Given that RTN expresses high levels of Kv3.1, with little or no Kv3.2, we tested whether this subunit was required for the fast action potential repolarization mechanism essential to the FS phenotype. Single- and multiple-action potentials were recorded using whole-cell current clamp in RTN neurons from brain slices of wild-type and Kv3.1-deficient mice. At 23°C, action potentials recorded from homozygous Kv3.1 deficient mice (Kv3.1−/−) compared with their wild-type (Kv3.1+/+) counterparts had reduced amplitudes (−6%) and fast after-hyperpolarizations (−16%). At 34°C, action potentials in Kv3.1−/− mice had increased duration (21%) due to a reduced rate of repolarization (−30%) when compared with wild-type controls. Action potential trains in Kv3.1−/− were associated with a significantly greater spike decrement and broadening and a diminished firing frequency versus injected current relationship ( F/I) at 34°C. There was no change in either spike count or maximum instantaneous frequency during low-threshold Ca2+ bursts in Kv3.1−/− RTN neurons at either temperature tested. Our findings show that Kv3.1 is not solely responsible for fast spikes or high-frequency firing in RTN neurons. This suggests genetic redundancy in the system, possibly in the form of other Kv3 members, which may suffice to maintain the FS phenotype in RTN neurons in the absence of Kv3.1.

Function of Specific K+ Channels in Sustained High-Frequency Firing of Fast-Spiking Neocortical Interneurons

1999 ◽  
Vol 82 (5) ◽  
pp. 2476-2489 ◽  
Author(s):  
A. Erisir ◽  
D. Lau ◽  
B. Rudy ◽  
C. S. Leonard
Keyword(s):  
Firing Rate ◽  
High Frequency ◽  
Spike Trains ◽  
Firing Frequency ◽  
Channel Inactivation ◽  
Spike Shape ◽  
Fast Spiking ◽  
Firing Properties ◽  
Action Potential Repolarization

Fast-spiking GABAergic interneurons of the neocortex and hippocampus fire high-frequency trains of brief action potentials with little spike-frequency adaptation. How these striking properties arise is unclear, although recent evidence suggests K+ channels containing Kv3.1-Kv3.2 proteins play an important role. We investigated the role of these channels in the firing properties of fast-spiking neocortical interneurons from mouse somatosensory cortex using a pharmacological and modeling approach. Low tetraethylammonium (TEA) concentrations (≤1 mM), which block only a few known K+channels including Kv3.1-Kv3.2, profoundly impaired action potential repolarization and high-frequency firing. Analysis of the spike trains evoked by steady depolarization revealed that, although TEA had little effect on the initial firing rate, it strongly reduced firing frequency later in the trains. These effects appeared to be specific to Kv3.1 and Kv3.2 channels, because blockade of dendrotoxin-sensitive Kv1 channels and BK Ca2+-activated K+ channels, which also have high TEA sensitivity, produced opposite or no effects. Voltage-clamp experiments confirmed the presence of a Kv3.1-Kv3.2–like current in fast-spiking neurons, but not in other interneurons. Analysis of spike shape changes during the spike trains suggested that Na+ channel inactivation plays a significant role in the firing-rate slowdown produced by TEA, a conclusion that was supported by computer simulations. These findings indicate that the unique properties of Kv3.1-Kv3.2 channels enable sustained high-frequency firing by facilitating the recovery of Na+ channel inactivation and by minimizing the duration of the afterhyperpolarization in neocortical interneurons.

Multiple potassium conductances and their role in action potential repolarization and repetitive firing behavior of neonatal rat hypoglossal motoneurons

1993 ◽  
Vol 69 (6) ◽  
pp. 2150-2163 ◽  
Author(s):  
F. Viana ◽  
D. A. Bayliss ◽  
A. J. Berger
Keyword(s):  
Action Potential ◽  
Calcium Influx ◽  
Potassium Conductance ◽  
Firing Frequency ◽  
Neonatal Rat ◽  
Repetitive Firing ◽  
Firing Behavior ◽  
Hypoglossal Motoneurons ◽  
Potassium Conductances ◽  
Action Potential Repolarization

1. The role of multiple potassium conductances in action potential repolarization and repetitive firing behavior of hypoglossal motoneurons was investigated using intracellular recording techniques in a brain stem slice preparation of the neonatal rat (0-15 days old). 2. The action potential was followed by two distinct afterhyperpolarizations (AHPs). The early one was of short duration and is termed the fAHP; the later AHP was of longer duration and is termed the mAHP. The amplitudes of both AHPs were enhanced by membrane potential depolarization (further from EK). In addition, their amplitudes were reduced by high extracellular K+ concentration, suggesting that activation of potassium conductances underlies both phases of the AHP. 3. Prolongation of the action potential and blockade of the fAHP were observed after application of 1) tetraethylammonium (TEA) (1-10 mM) and 2) 4-aminopyridine (4-AP) (0.1-0.5 mM). Calcium channel blockers had little or no effect on the fAHP or action potential duration. 4. The size of the mAHP was diminished by 1) manganese, 2) lowering external Ca2+, 3) apamin, and 4) intracellular injection of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) suggesting that influx of calcium activates the potassium conductance that underlies the mAHP. 5. The mAHP was unaffected by nifedipine (20 microM), but was strongly reduced by focal application of omega-conotoxin GVIA, suggesting that N-type calcium channels represent the major calcium influx pathway for activation of the calcium-dependent K+ conductance underlying the mAHP. 6. Repetitive firing properties were investigated by injecting long-duration depolarizing current pulses. Steady-state firing rose linearly with injected current amplitude. The slope of the firing frequency-current (f-I) relationship averaged approximately 30 Hz/nA in control conditions. Blockade of the conductance underlying the mAHP caused a marked increase in the minimal repetitive firing frequency and in the slope of the f-I plot, indicating a prominent role for the conductance underlying the mAHP in controlling repetitive firing behavior. 7. We conclude that action potential repolarization and AHPs are due to activation of pharmacologically distinct potassium conductances. Whereas repolarization of the action potential and the fAHP involves primarily a voltage-dependent, calcium-independent potassium conductance that is TEA- and 4-AP-sensitive, the mAHP requires the influx of extracellular calcium and is apamin sensitive. Activation of the calcium-activated potassium conductance greatly influences the normal repetitive firing of neonatal hypoglossal motoneurons.

Changes in ventricular repolarization during acidosis and low-flow ischemia

1998 ◽  
Vol 275 (2) ◽  
pp. H551-H561 ◽  
Author(s):  
Hugh W. L. Bethell ◽  
Jamie I. Vandenberg ◽  
Gerry A. Smith ◽  
Andrew A. Grace
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Respiratory Acidosis ◽  
Control Flow ◽  
Low Flow ◽  
Channel Blockers ◽  
Monophasic Action Potentials ◽  
Ferret Heart ◽  
Action Potential Repolarization ◽  
Intact Heart

Myocardial ischemia, primarily a metabolic insult, is also defined by altered cardiac mechanical and electrical activity. We have investigated the metabolic contributions to the electrophysiological changes during low-flow ischemia (7.5% of the control flow) using31P NMR spectroscopy to monitor metabolic parameters, suction electrodes to study epicardial monophasic action potentials, and 86Rb as a tracer for K+-equivalent efflux during low-flow ischemia in the Langendorff-perfused ferret heart. Shortening of the action potential duration at 90% repolarization (APD90) was most marked between 1 and 5 min after induction of ischemia, at which time it shortened from 261 ± 4 to 213 ± 8 ms. The period of marked APD90 shortening was accompanied by a fivefold increase in the rate of86Rb efflux, both of which were inhibited by the ATP-sensitive K+(KATP)-channel blockers glibenclamide and 5-hydroxydecanoate (5-HD), as well as by a significant fall in intracellular pH (pHi) from 7.14 ± 0.02 to 6.83 ± 0.03 but no change in intracellular ATP concentration ([ATP]i). We therefore investigated whether a fall in pHi could be the metabolic change responsible for modulating cardiac KATP channel activity in the intact heart during ischemia. Both metabolic (30 mM lactate added to extracellular solution) and respiratory ([Formula: see text] increased to 15%) acidosis caused an initial lengthening of APD90 to 112 ± 1.5 and 113 ± 0.9%, respectively, followed by shortening during continued acidosis to 106 ± 1.2 and 106 ± 1.4%, respectively. The shortening of APD90 during continued acidosis was inhibited by glibenclamide, consistent with acidosis causing activation of KATP channels at normal [ATP]i. The similar responses to metabolic (induced by adding either l- or d-lactate) and respiratory acidosis suggest that lactate has no independent metabolic effect on action potential repolarization.

Synaptic Activation of Dendritic AMPA and NMDA Receptors Generates Transient High-Frequency Firing in Substantia Nigra Dopamine Neurons In Vitro

2007 ◽  
Vol 97 (4) ◽  
pp. 2837-2850 ◽  
Author(s):  
Sarah N. Blythe ◽  
Jeremy F. Atherton ◽  
Mark D. Bevan
Keyword(s):  
Nmda Receptor ◽  
Substantia Nigra ◽  
Action Potential ◽  
Nmda Receptors ◽  
High Frequency ◽  
Brain Slices ◽  
Dopamine Neurons ◽  
Frequency Pattern ◽  
High Frequency Activity ◽  
Evoked Activity

Transient high-frequency activity of substantia nigra dopamine neurons is critical for striatal synaptic plasticity and associative learning. However, the mechanisms underlying this mode of activity are poorly understood because, in contrast to other rapidly firing neurons, high-frequency activity is not evoked by somatic current injection. Previous studies have suggested that activation of dendritic N-methyl-d-aspartate (NMDA) receptors and/or G-protein-coupled receptor (GPCR)-mediated reduction of action potential afterhyperpolarization and/or activation of cation channels underlie high-frequency activity. To address their relative contribution, transient high-frequency activity was evoked using local electrical stimulation (1 s, 10–100 Hz) in brain slices prepared from p15–p25 rats in the presence of GABA and D2 dopamine receptor antagonists. The frequency, pattern, and morphology of action potentials evoked under these conditions were similar to those observed in vivo. Evoked activity and reductions in action potential afterhyperpolarization were diminished greatly by application of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or NMDA receptor selective antagonists and abolished completely by co-application of AMPA and NMDA antagonists. In contrast, application of glutamatergic and cholinergic GPCR antagonists moderately enhanced evoked activity. Dendritic pressure-pulse application of glutamate evoked high-frequency activity that was similarly sensitive to antagonism of AMPA or NMDA receptors. Taken together, these data suggest that dendritic AMPA and NMDA receptor-mediated synaptic conductances are sufficient to generate transient high-frequency activity in substantia nigra dopamine neurons by rapidly but transiently overwhelming the conductances underlying action potential afterhyperpolarization and/or engaging postsynaptic voltage-dependent ion channels in a manner that overcomes the limiting effects of afterhyperpolarization.

scholarly journals Large, stable spikes exhibit differential broadening in excitatory and inhibitory neocortical boutons

2020 ◽  
Author(s):  
Andreas Ritzau-Jost ◽  
Timur Tsintsadze ◽  
Martin Krueger ◽  
Jonas Ader ◽  
Ingo Bechmann ◽  
...  
Keyword(s):  
Patch Clamp ◽  
High Frequency ◽  
Neurotransmitter Release ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Cultured Neurons ◽  
Presynaptic Action ◽  
Presynaptic Spike ◽  
Fast Spiking

SUMMARYPresynaptic action potential spikes control neurotransmitter release and thus interneuronal communication. However, the properties and the dynamics of presynaptic spikes in the neocortex remain enigmatic because boutons in the neocortex are small and direct patch-clamp recordings have not been performed. Here we report direct recordings from boutons of neocortical pyramidal neurons and interneurons. Our data reveal rapid and large presynaptic action potentials in layer 5 neurons and fast-spiking interneurons reliably propagating into axon collaterals. For in-depth analyses we validate boutons of mature cultured neurons as models for excitatory neocortical boutons, demonstrating that the presynaptic spike amplitude was unaffected by potassium channels, homeostatic long-term plasticity, and high-frequency firing. In contrast to the stable amplitude, presynaptic spikes profoundly broadened for example during high-frequency firing in layer 5 pyramidal neurons but not in fast-spiking interneurons. Thus, our data demonstrate large presynaptic spikes and fundamental differences between excitatory and inhibitory boutons in the neocortex.

Low-Voltage-Activated Calcium Current Does Not Regulate the Firing Behavior in Paired Mechanosensory Neurons With Different Adaptation Properties

2000 ◽  
Vol 83 (2) ◽  
pp. 746-753 ◽  
Author(s):  
Shin-Ichi Sekizawa ◽  
Andrew S. French ◽  
Päivi H. Torkkeli
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Low Voltage ◽  
Firing Frequency ◽  
Oscillatory Behavior ◽  
Firing Behavior ◽  
Single Action ◽  
Synaptic Excitation ◽  
Intracellular Ca ◽  
The Difference

Low-voltage-activated Ca2+ currents (LVA- I Ca) are believed to perform several roles in neurons such as lowering the threshold for action potentials, promoting burst firing and oscillatory behavior, and enhancing synaptic excitation. They also may allow rapid increases in intracellular Ca2+ concentration. We discovered LVA- I Ca in both members of paired mechanoreceptor neurons in a spider, where one neuron adapts rapidly (Type A) and the other slowly (Type B) in response to a step stimulus. To learn if I Ca contributed to the difference in adaptation behavior, we studied the kinetics of I Ca from isolated somata under single-electrode voltage-clamp and tested its physiological function under current clamp. LVA- I Ca was large enough to fire single action potentials when all other voltage-activated currents were blocked, but we found no evidence that it regulated firing behavior. LVA- I Ca did not lower the action potential threshold or affect firing frequency. Previous experiments have failed to find Ca2+-activated K+ current ( I K(Ca)) in the somata of these neurons, so it is also unlikely that LVA- I Ca interacts with I K(Ca) to produce oscillatory behavior. We conclude that LVA-Ca2+ channels in the somata, and possible in the dendrites, of these neurons open in response to the depolarization caused by receptor current and by the voltage-activated Na+ current ( I Na) that produces action potential(s). However, the role of the increased intracellular Ca2+ concentration in neuronal function remains enigmatic.

Lack of Depolarization-Induced Suppression of Inhibition (DSI) in Layer 2/3 Interneurons That Receive Cannabinoid-Sensitive Inhibitory Inputs

2007 ◽  
Vol 98 (5) ◽  
pp. 2517-2524 ◽  
Author(s):  
Fouad Lemtiri-Chlieh ◽  
Eric S. Levine
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Brain Slices ◽  
Gaba Release ◽  
Synaptic Activity ◽  
Layer 2 ◽  
Fast Spiking ◽  
Whole Cell Recordings

In layer 2/3 of neocortex, brief trains of action potentials in pyramidal neurons (PNs) induce the mobilization of endogenous cannabinoids (eCBs), resulting in a depression of GABA release from the terminals of inhibitory interneurons (INs). This depolarization-induced suppression of inhibition (DSI) is mediated by activation of the type 1 cannabinoid receptor (CB1) on presynaptic terminals of a subset of INs. However, it is not clear whether CB1 receptors are also expressed at synapses between INs, and whether INs can release eCBs in response to depolarization. In the present studies, brain slices containing somatosensory cortex were prepared from 14- to 21-day-old CD-1 mice. Whole cell recordings were obtained from layer 2/3 PNs and from INs classified as regular spiking nonpyramidal, irregular spiking, or fast spiking. For all three classes of INs, the cannabinoid agonist WIN55,212-2 suppressed inhibitory synaptic activity, similar to the effect seen in PNs. In addition, trains of action potentials in PNs resulted in significant DSI. In INs, however, DSI was not seen in any cell type, even with prolonged high-frequency spike trains that produced calcium increases comparable to that seen with DSI induction in PNs. In addition, blocking eCB reuptake with AM404, which enhanced DSI in PNs, failed to unmask any DSI in INs. Thus the lack of DSI in INs does not appear to be due to an insufficient increase in intracellular calcium or enhanced reuptake. These results suggest that layer 2/3 INs receive CB1-expressing inhibitory inputs, but that eCBs are not released by these INs.

scholarly journals Frequency-dependent entrainment of striatal fast-spiking interneurons

2019 ◽  
Vol 122 (3) ◽  
pp. 1060-1072 ◽  
Author(s):  
Matthew H. Higgs ◽  
Charles J. Wilson
Keyword(s):  
Action Potentials ◽  
Frequency Tuning ◽  
Brain Slices ◽  
Stimulus Frequency ◽  
Broadband Noise ◽  
Constant Current ◽  
Phase Resetting ◽  
Gamma Frequency ◽  
Frequency Components ◽  
Fast Spiking

Striatal fast-spiking interneurons (FSIs) fire in variable-length runs of action potentials at 20–200 spikes/s separated by pauses. In vivo, or with fluctuating applied current, both runs and pauses become briefer and more variable. During runs, spikes are entrained specifically to gamma-frequency components of the input fluctuations. We stimulated parvalbumin-expressing striatal FSIs in mouse brain slices with broadband noise currents added to direct current steps and measured spike entrainment across all frequencies. As the constant current level was increased, FSIs produced longer runs and showed sharper frequency tuning, with best entrainment at the stimulus frequency matching their intrarun firing rate. We separated the contributions of previous spikes from that of the fluctuating stimulus, revealing a strong contribution of previous action potentials to gamma-frequency entrainment. In contrast, after subtraction of the effect inherited from the previous spike, the remaining stimulus contribution to spike generation was less sharply tuned, showing a larger contribution of lower frequencies. The frequency specificity of entrainment within a run was reproduced with a phase resetting model based on experimentally measured phase resetting curves of the same FSIs. In the model, broadly tuned phase entrainment for the first spike in a run evolved into sharply tuned gamma entrainment over the next few spikes. The data and modeling results indicate that for FSIs firing in brief runs and pauses firing within runs is entrained by gamma-frequency components of the input, whereas the onset timing of runs may be sensitive to a wider range of stimulus frequency components. NEW & NOTEWORTHY Specific types of neurons entrain their spikes to particular oscillation frequencies in their synaptic input. This entrainment is commonly understood in terms of the subthreshold voltage response, but how this translates to spiking is not clear. We show that in striatal fast-spiking interneurons, entrainment to gamma-frequency input depends on rhythmic spike runs and is explained by the phase resetting curve, whereas run initiation can be triggered by a broad range of input frequencies.

Fluorescence imaging of cardiac propagation: spectral properties and filtering of optical action potentials

2006 ◽  
Vol 291 (1) ◽  
pp. H327-H335 ◽  
Author(s):  
Sergey F. Mironov ◽  
Frederick J. Vetter ◽  
Arkady M. Pertsov
Keyword(s):  
Action Potential ◽  
Wave Front ◽  
Fluorescence Imaging ◽  
High Frequency ◽  
Action Potentials ◽  
High Signal ◽  
Fluorescence Signal ◽  
Signal To Noise ◽  
Right Ventricular Free Wall ◽  
Spectral Components

Fluorescence imaging using voltage-sensitive dyes is an important tool for studying electrical propagation in the heart. Yet, the low amplitude of the voltage-sensitive component in the fluorescence signal and high acquisition rates dictated by the rapid propagation of the excitation wave front make it difficult to achieve recordings with high signal-to-noise ratios. Although spatially and temporally filtering the acquired signals has become de facto one of the key elements of optical mapping, there is no consensus regarding their use. Here we characterize the spatiotemporal spectra of optically recorded action potentials and determine the distortion produced by conical filters of different sizes. On the basis of these findings, we formulate the criteria for rational selection of filter characteristics. We studied the evolution of the spatial spectra of the propagating wave front after epicardial point stimulation of the isolated, perfused right ventricular free wall of the pig heart stained with di-4-ANEPPS. We found that short-wavelength (<3 mm) spectral components represent primarily noise and surface features of the preparation (coronary vessels, fat, and connective tissue). The time domain of the optical action potential spectrum also lacks high-frequency components (>100 Hz). Both findings are consistent with the reported effect of intrinsic blurring caused by light scattering inside the myocardial wall. The absence of high-frequency spectral components allows the use of aggressive low-pass spatial and temporal filters without affecting the optical action potential morphology. We show examples where the signal-to-noise ratio increased up to 150 with <3% distortion. A generalization of our approach to the rational filter selection in various applications is discussed.

Potassium currents contributing to action potential repolarization and the afterhyperpolarization in rat vagal motoneurons

1992 ◽  
Vol 68 (5) ◽  
pp. 1834-1841 ◽  
Author(s):  
P. Sah ◽  
E. M. McLachlan
Keyword(s):  
Action Potential ◽  
Time Constant ◽  
Action Potentials ◽  
Potassium Current ◽  
Outward Current ◽  
Potassium Currents ◽  
Membrane Potentials ◽  
Calcium Currents ◽  
Resting Potential ◽  
Action Potential Repolarization

1. Intracellular recordings were made from neurons in the dorsal motor nucleus of the vagus (DMV) in transverse slices of rat medulla maintained in vitro at 30 degrees C. Neurons had a resting potential of -59.8 +/- 1.4 (SE) mV (n = 39) and input resistance of 293 +/- 23 M omega (n = 44). 2. Depolarization elicited overshooting action potentials that were blocked by tetrodotoxin (TTX; 1 microM). In the presence of TTX, two types of action potentials having low and high thresholds could be elicited. The action potentials were blocked by cobalt (2 mM) indicating they were mediated by calcium currents. 3. Under voltage clamp, depolarization of the cell from membrane potentials negative of the resting potential activated a transient potassium current. This current was selectively blocked by 4-aminopyridine (4-AP) (5 mM) and catechol (5 mM) indicating that it is an A-type current. This current inactivated with a time constant of 420 ms and recovered from inactivation with a time constant of 26 ms. 4. When calcium currents were blocked by cadmium or cobalt, the rate of action potential repolarization was slower. In the presence of tetraethylammonium (TEA; 200-400 microM) or charybdotoxin (CTX; 30 nM) a small "hump" appeared on the repolarizing phase of the action potential that was abolished by addition of cadmium. These results indicate that a calcium-activated potassium current (IC) contributes to action potential repolarization. 5. Actions potentials elicited from hyperpolarized membrane potentials repolarized faster than those elicited from resting membrane potential. This effect could be blocked by catechol, indicating that voltage-dependent potassium currents (IA) can also contribute to action-potential repolarization. In the presence of catechol and calcium channel blockers, action potentials still had a significant early afterhyperpolarization suggesting that another calcium independent outward current is also active during repolarization. This fast afterhyperpolarizations (AHP) was not blocked by TEA. 6. Action potentials were followed by prolonged AHPs, which had two phases. The initial part of the AHP was blocked by apamin (100 nM) indicating that it results from activation of SK type calcium-activated potassium channels. The slow phase was selectively blocked by catechol suggesting that it is due to activation of IA. 7. It is concluded that a TTX-sensitive sodium current and two calcium currents contribute to the action potential in rat DMV neurons. At least three different currents contribute to action-potential repolarization: IC, IA, and a third unidentified calcium-insensitive outward current.(ABSTRACT TRUNCATED AT 400 WORDS)

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