The potassium A-current,low firing rates and rebound excitation in Hodgkin-Huxley models

It is widely believed, following the work of Connor and Stevens (1971,J. Physiol. Lond. 214, 31–53) that the ability to fire action potentials over a wide frequency range, especially down to very low rates, is due to the transient, potassium A-current (I _A). Using a reduction of the classical Hodgkin-Huxley model, we study the effects ofI _A on steady firing rate, especially in the near-threshold regime for the onset of firing. A minimum firing rate of zero corresponds to a homoclinic bifurcation of periodic solutions at a critical level of stimulating current. It requires that the membrane's steady-state current-voltage relation be N-shaped rather than monotonic. For experimentally based genericI _A parameters, the model does not fire at arbitrarily low rates, although it can for the more atypicalI _A parameters given by Connor and Stevens for the crab axon. When theI _A inactivation rate is slow, we find that the transient potassium current can mediate more complex firing patterns, such as periodic bursting in some parameter regimes. The number of spikes per burst increases asg _A decreases and as inactivation rate decreases. We also study howI _A affects properties of transient voltage responses, such as threshold and firing latency for anodal break excitation. We provide mathematical explanations for several of these dynamic behaviors using bifurcation theory and averaging methods.     

Ionic currents influencing spontaneous firing and pacemaker frequency in dopamine neurons of the ventrolateral periaqueductal gray and dorsal raphe nucleus (vlPAG/DRN): A voltage-clamp and computational modelling study

Dopamine (DA) neurons of the ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus (DRN) fire spontaneous action potentials (APs) at slow, regular patterns in vitro but a detailed account of their intrinsic membrane properties responsible for spontaneous firing is currently lacking. To resolve this, we performed a voltage-clamp electrophysiological study in brain slices to describe their major ionic currents and then constructed a computer model and used simulations to understand the mechanisms behind autorhythmicity in silico. We found that vlPAG/DRN DA neurons exhibit a number of voltage-dependent currents activating in the subthreshold range including, a hyperpolarization-activated cation current (I_H), a transient, A-type, potassium current (I_A), a background, ‘persistent’ (I_NaP) sodium current and a transient, low voltage activated (LVA) calcium current (I_CaLVA). Brain slice pharmacology, in good agreement with computer simulations, showed that spontaneous firing occurred independently of I_H, I_A or calcium currents. In contrast, when blocking sodium currents, spontaneous firing ceased and a stable, non-oscillating membrane potential below AP threshold was attained. Using the DA neuron model we further show that calcium currents exhibit little activation (compared to sodium) during the interspike interval (ISI) repolarization while, any individual potassium current alone, whose blockade positively modulated AP firing frequency, is not required for spontaneous firing. Instead, blockade of a number of potassium currents simultaneously is necessary to eliminate autorhythmicity. Repolarization during ISI is mediated initially via the deactivation of the delayed rectifier potassium current, while a sodium background ‘persistent’ current is essentially indispensable for autorhythmicity by driving repolarization towards AP threshold.     

Forskolin Suppresses Delayed-Rectifier K+ Currents and Enhances Spike Frequency-Dependent Adaptation of Sympathetic Neurons

In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K⁺ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K⁺ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K⁺ current (I_KV). Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that I_KV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K⁺ currents. Forskolin inhibited Kv2.1 currents and I_KV with an IC₅₀ of ~32 μM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels.     

Shal/K(v)4 channels are required for maintaining excitability during repetitive firing and normal locomotion in Drosophila

Background

Rhythmic behaviors, such as walking and breathing, involve the coordinated activity of central pattern generators in the CNS, sensory feedback from the PNS, to motoneuron output to muscles. Unraveling the intrinsic electrical properties of these cellular components is essential to understanding this coordinated activity. Here, we examine the significance of the transient A-type K⁺ current (I_A), encoded by the highly conserved Shal/K_v4 gene, in neuronal firing patterns and repetitive behaviors. While I_A is present in nearly all neurons across species, elimination of I_A has been complicated in mammals because of multiple genes underlying I_A, and/or electrical remodeling that occurs in response to affecting one gene.

Methodology/Principal Findings

In Drosophila, the single Shal/K_v4 gene encodes the predominant I_A current in many neuronal cell bodies. Using a transgenically expressed dominant-negative subunit (DNK_v4), we show that I_A is completely eliminated from cell bodies, with no effect on other currents. Most notably, DNK_v4 neurons display multiple defects during prolonged stimuli. DNK_v4 neurons display shortened latency to firing, a lower threshold for repetitive firing, and a progressive decrement in AP amplitude to an adapted state. We record from identified motoneurons and show that Shal/K_v4 channels are similarly required for maintaining excitability during repetitive firing. We then examine larval crawling, and adult climbing and grooming, all behaviors that rely on repetitive firing. We show that all are defective in the absence of Shal/K_v4 function. Further, knock-out of Shal/K_v4 function specifically in motoneurons significantly affects the locomotion behaviors tested.

Conclusions/Significance

Based on our results, Shal/K_v4 channels regulate the initiation of firing, enable neurons to continuously fire throughout a prolonged stimulus, and also influence firing frequency. This study shows that Shal/K_v4 channels play a key role in repetitively firing neurons during prolonged input/output, and suggests that their function and regulation are important for rhythmic behaviors.     

The role of a transient potassium current in a bursting neuron model

Presented here is a biophysical cell model which can exhibit low-frequency repetitive activity and bursting behavior. The model is developed from previous models (Av-Ron et al. 1991, 1993) for excitability, oscillations and bursting. A stepwise development of the present model shows the contribution of a transient potassium current (I _A ) to the overall dynamics. By changing a limited set of model parameters one can describe different firing patterns; oscillations with frequencies ranging from 2–200 Hz and a wide range of bursting behaviors in terms of the durations of bursting and quiescence, peak firing frequency and rate of change of the firing frequency.     

Low dose of dopamine may stimulate prolactin secretion by increasing fast potassium currents

Dopamine (DA) released from the hypothalamus tonically inhibits pituitary lactotrophs. DA (at micromolar concentration) opens potassium channels, hyperpolarizing the lactotrophs and thus preventing the calcium influx that triggers prolactin hormone release. Surprisingly, at concentrations ∼1000 lower, DA can stimulate prolactin secretion. Here, we investigated whether an increase in a K⁺ current could mediate this stimulatory effect. We considered the fast K⁺ currents flowing through large-conductance BK channels and through A-type channels. We developed a minimal lactotroph model to investigate the effects of these two currents. Both I _BK and I _A could transform the electrical pattern of activity from spiking to bursting, but through distinct mechanisms. I _BK always increased the intracellular Ca²⁺ concentration, while I _A could either increase or decrease it. Thus, the stimulatory effects of DA could be mediated by a fast K⁺ conductance which converts tonically spiking cells to bursters. In addition, the study illustrates that a heterogeneous distribution of fast K⁺ conductances could cause heterogeneous lactotroph firing patterns. Action Editor: Christiane Linster     

Intrinsic bursting activity in the pre-Bötzinger Complex: Role of persistent sodium and potassium currents

Computational models of single pacemaker neuron and neural population in the pre-Bötzinger Complex (pBC) were developed based on the previous models by Butera et al. (1999a,b). Our modeling study focused on the conditions that could define endogenous bursting vs. tonic activity in single pacemaker neurons and population bursting vs. asynchronous firing in populations of pacemaker neurons. We show that both bursting activity in single pacemaker neurons and population bursting activity may be released or suppressed depending on the expression of persistent sodium (I_NaP) and delayed-rectifier potassium (I_K) currents. Specifically, a transition from asynchronous firing to population bursting could be induced by a reduction of I_K via a direct suppression of the potassium conductance or through an elevation of extracellular potassium concentration. Similar population bursting activity could be triggered by an augmentation of I_NaP. These findings are discussed in the context of the possible role of population bursting activity in the pBC in the respiratory rhythm generation in vivo vs. in vitro and during normal breathing in vivo vs. gasping.     

Phase-resetting curve determines how BK currents affect neuronal firing

BK channels are large conductance potassium channels gated by calcium and voltage. Paradoxically, blocking these channels has been shown experimentally to increase or decrease the firing rate of neurons, depending on the neural subtype and brain region. The mechanism for how this current can alter the firing rates of different neurons remains poorly understood. Using phase-resetting curve (PRC) theory, we determine when BK channels increase or decrease the firing rates in neural models. The addition of BK currents always decreases the firing rate when the PRC has only a positive region. When the PRC has a negative region (type II), BK currents can increase the firing rate. The influence of BK channels on firing rate in the presence of other conductances, such as I _m and I _h , as well as with different amplitudes of depolarizing input, were also investigated. These results provide a formal explanation for the apparently contradictory effects of BK channel antagonists on firing rates.     

Differential contributions of somatic and dendritic calcium-dependent potassium currents to the control of motoneuron excitability following spinal cord injury

The hyperexcitability of alpha-motoneurons and accompanying spasticity following spinal cord injury (SCI) have been attributed to enhanced persistent inward currents (PICs), including L-type calcium and persistent sodium currents. Factors controlling PICs may offer new therapies for managing spasticity. Such factors include calcium-activated potassium (KCa) currents, comprising in motoneurons an after-hyperpolarization-producing current (I _KCaN) activated by N/P-type calcium currents, and a second current (I _KCaL) activated by L-type calcium currents (Li and Bennett in J neurophysiol 97:767–783, 2007). We hypothesize that these two currents offer differential control of PICs and motoneuron excitability based on their probable somatic and dendritic locations, respectively. We reproduced SCI-induced PIC enhancement in a two-compartment motoneuron model that resulted in persistent dendritic plateau potentials. Removing dendritic I _KCaL eliminated primary frequency range discharge and produced an abrupt transition into tertiary range firing without significant changes in the overall frequency gain. However, I _KCaN removal mainly increased the gain. Steady-state analyses of dendritic membrane potential showed that I _KCaL limits plateau potential magnitude and strongly modulates the somatic injected current thresholds for plateau onset and offset. In contrast, I _KCaN had no effect on the plateau magnitude and thresholds. These results suggest that impaired function of I _KCaL may be an important intrinsic mechanism underlying PIC-induced motoneuron hyperexcitability following SCI.     

Effects of Estradiol on Voltage-Gated Potassium Channels in Mouse Dorsal Root Ganglion Neurons

Voltage-gated potassium channels are regulators of membrane potentials, action potential shape, firing adaptation, and neuronal excitability in excitable tissues including in the primary sensory neurons of dorsal root ganglion (DRG). In this study, using the whole-cell patch-clamp technique, the effect of estradiol (E2) on voltage-gated total outward potassium currents, the component currents transient “A-type” current (I _A) currents, and “delayed rectifier type” (I _KDR) currents in isolated mouse DRG neurons was examined. We found that the extracellularly applied 17β-E2 inhibited voltage-gated total outward potassium currents; the effects were rapid, reversible, and concentration-dependent. Moreover, the membrane impermeable E2-BSA was as efficacious as 17β-E2, whereas 17α-E2 had no effect. 17β-E2-stimulated decrease in the potassium current was unaffected by treatment with ICI 182780 (classic estrogen receptor antagonist), actinomycin D (RNA synthesis inhibitor), or cycloheximide (protein synthesis inhibitor). We also found that I _A and I _KDR were decreased after 17β-E2 application. 17β-E2 significantly shifted the activation curve for I _A and I _KDR channels in the hyperpolarizing direction. In conclusion, our results demonstrate that E2 inhibited voltage-gated K⁺ channels in mouse DRG neurons through a membrane ER-activated non-genomic pathway.     

Sodium Metabisulfite Modulation of Potassium Channels in Pain-Sensing Dorsal Root Ganglion Neurons

The effects of sodium metabisulfite (SMB), a general food preservative, on potassium currents in rat dorsal root ganglion (DRG) neurons were investigated using the whole-cell patch-clamp technique. SMB increased the amplitudes of both transient outward potassium currents and delayed rectifier potassium current in concentration- and voltage-dependent manner. The transient outward potassium currents (TOCs) include a fast inactivating (A-current or I _A) current and a slow inactivating (D-current or I _D) current. SMB majorly increased I_A, and I_D was little affected. SMB did not affect the activation process of transient outward currents (TOCs), but the inactivation curve of TOCs was shifted to more positive potentials. The inactivation time constants of TOCs were also increased by SMB. For delayed rectifier potassium current (I _K), SMB shifted the activation curve to hyperpolarizing direction. SMB differently affected TOCs and I _K, its effects major on A-type K⁺ channels, which play a role in adjusting pain sensitivity in response to peripheral redox conditions. SMB did not increase TOCs and I _K when adding DTT in pipette solution. These results suggested that SMB might oxidize potassium channels, which relate to adjusting pain sensitivity in pain-sensing DRG neurons.     

An Ionic Current Model for Medullary Respiratory Neurons

Neurons of the mammalian medullary respiratory center have complex patterns of electrophysiological behavior. Three typical phenomena associated with these patterns are spike frequency adaptation (SFA), delayed excitation (DE), and postinhibitory rebound (PIR). Although several nuclei are associated with the medullary-pontine respiratory center, we focused on neurons from two nuclei: (1) the ventral subnucleus of the nucleus tractus solitarius (vNTS) of the dorsal respiratory group and (2) the nucleus ambiguus (NA) of the ventral respiratory group. We developed a Hodgkin-Huxley (HH) type model of the typical medullary neuron that is capable of mimicking the discharge pattern of real neurons to a very high degree. Closer examination of typical data revealed, however, that there was not one type of medullary respiratory neuron, but at least three (types A, B ₁, and B ₂). We classified these neurons based on the electrophysiologic phenomena that they exhibited (type A exhibits DE but not PIR; types B ₁ and B ₂ exhibit PIR but not DE; all types are adapting). Our objective was to relate each of these well-known phenomena to specific ionic current mechanisms. In the model, three currents directly affect the phenomena investigated: the Ca²⁺-activated K ⁺ current, I _K,Ca , controls peak and steady-state firing rates and the time constant of adaptation; the transient outward K ⁺ current, I _A, is responsible for all aspects of DE, including the dependence of delay on the magnitude and duration of conditioning hyperpolarization; and the hyperpolarization-activated current, I _h, elicits PIR and dictates its dependencies. We consider that our HH model represents a unifying structure, whereby different electrophysiological phenomena or discharge patterns can be emulated using different strengths of the component ionic membrane currents (particularly I _K,Ca , I _A, and I _h). Moreover, its predictions suggest that the electrophysiological characteristics of medullary respiratory neurons, from different areas of the brainstem and even from different species, can be modeled using the same structural framework, wherein the specific properties of individual neurons are emulated by adjusting the strengths of key ionic membrane currents in the model.     

Impact of slow K<Superscript>+</Superscript> currents on spike generation can be described by an adaptive threshold model

A neuron that is stimulated by rectangular current injections initially responds with a high firing rate, followed by a decrease in the firing rate. This phenomenon is called spike-frequency adaptation and is usually mediated by slow K⁺ currents, such as the M-type K⁺ current (I _M ) or the Ca²⁺-activated K⁺ current (I _AHP ). It is not clear how the detailed biophysical mechanisms regulate spike generation in a cortical neuron. In this study, we investigated the impact of slow K⁺ currents on spike generation mechanism by reducing a detailed conductance-based neuron model. We showed that the detailed model can be reduced to a multi-timescale adaptive threshold model, and derived the formulae that describe the relationship between slow K⁺ current parameters and reduced model parameters. Our analysis of the reduced model suggests that slow K⁺ currents have a differential effect on the noise tolerance in neural coding.     

Voltage-activated lonic currents in differentiating rat cerebellar granule neurons cultured from the external germinal layer

The electrical properties of the precursor cells of the external germinal layer of rat cerebellum were assessed during their differentiation in control medium (Dulbecco's modified Eagle's medium) supplemented or not with either basic fibroblast growth factor (bFGF) or 25 mM potassium chloride (KCI). Resting potential was shown to be –10 mV in all three conditions 3 hours after plating [days in vitro (DIV)0]. By DIV 5, it reached -63 mV for cells cultured in 25 mM KCI but only –28 mV in control and bFGF media. The main voltage-sensitive ionic current measured at DIV 0 under all conditions was a composite I_k consisting in a sustained K⁺ current blocked by tetraethylammonium (I_k(TEA)), plus a rapidly activating and inactivating TEA-insensitive I_k(A). Both currents increased with time in all conditions, but after 5 days I_K(A) became dominant in terms of density. I_K(TEA) is likely an I_K(Ca), since it was blocked by 67% in 1 mM TEA. On DIV O, I_Na and I_Ca were absent or small in amplitude. By DIV 3, 80% of the cells had currents able to generate a spike. Interestingly, I_Ca mean amplitude and current density measured at –10 mV in control condition on DIV 1 was singnificantly larger than those recorded in bFGF and 25 mM KCI. The order of appearance of the ionic currents, I_K, I_Ca, and I_Na, leads directly to fast spike activity allowing for poor calcium entry. Firing rate likely depends on I_K(A), which increased during the first 6 days of development but could be differentially regulated by bFGF. © 1995 John Wiley & Sons, Inc.     

Subthreshold outward currents enhance temporal integration in auditory neurons

Many auditory neurons possess low-threshold potassium currents (I _KLT ) that enhance their responsiveness to rapid and coincident inputs. We present recordings from gerbil medial superior olivary (MSO) neurons in vitro and modeling results that illustrate how I _KLT improves the detection of brief signals, of weak signals in noise, and of the coincidence of signals (as needed for sound localization). We quantify the enhancing effect of I _KLT on temporal processing with several measures: signal-to-noise ratio (SNR), reverse correlation or spike-triggered averaging of input currents, and interaural time difference (ITD) tuning curves. To characterize how I _KLT , which activates below spike threshold, influences a neurons voltage rise toward threshold, i.e., how it filters the inputs, we focus first on the response to weak and noisy signals. Cells and models were stimulated with a computer-generated steady barrage of random inputs, mimicking weak synaptic conductance transients (the noise), together with a larger but still subthreshold postsynaptic conductance, EPSG (the signal). Reduction of I _KLT decreased the SNR, mainly due to an increase in spontaneous firing (more false positive). The spike-triggered reverse correlation indicated that I _KLT shortened the integration time for spike generation. I _KLT also heightened the models timing selectivity for coincidence detection of simulated binaural inputs. Further, ITD tuning is shifted in favor of a slope code rather than a place code by precise and rapid inhibition onto MSO cells (Brand et al. 2002). In several ways, low-threshold outward currents are seen to shape integration of weak and strong signals in auditory neurons.     

Sizing the radius of the pore formed in erythrocytes and lipid vesicles by the toxin sticholysin I from the sea anemone Stichodactyla helianthus

Tamoxifen (tmx) is a non-steroidal triphenylethylene derivative that is predominantly known as a competitive antagonist at the estrogen receptor and is used in the treatment of breast cancer. Recent studies suggest that tamoxifen is also beneficial in the treatment of brain metastases and primary brain tumors. Tmx accumulates in brain and its concentration can be up to 46-fold higher than in serum. Therefore, astrocytes may be exposed to tmx in vivo. We use the whole-cell patch-clamp technique to examine the effects of tmx on voltage-dependent cation currents in rat cortical cultures. Using biophysical and pharmacological methods, we isolate sustained and transient outward potassium currents (I _KS and I _KT , respectively), inwardly rectifying potassium currents (I _KIR ), and transient inward sodium currents (I _Na ). We show that that TTX-sensitive I _Na is completely inhibited by 10 μm tmx within 5 min. Similarly, tmx blocks I _KS , but does not inhibit I _KT or I _KIR at these concentrations. Tmx effects are irreversible with 10 min wash. Interestingly, the currents sensitive to tmx are important in growth control of glial cells (MacFarlane & Sontheimer, 1997). Therefore, we examine cytotoxic and proliferative effects of tmx. Tmx (10 μm) is not cytotoxic as judged by trypan blue exclusion. However, incubation with tmx significantly reduces cell proliferation as examined by ³[H]-thymidine uptake. Received: 12 October 2000/Revised: 12 February 2001     

Electrophysiological Evidence for Intrinsic Pacemaker Currents in Crayfish Parasol Cells

I used sharp intracellular electrodes to record from parasol cells in the semi-isolated crayfish brain to investigate pacemaker currents. Evidence for the presence of the hyperpolarization-activated inward rectifier potassium current was obtained in about half of the parasol cells examined, where strong, prolonged hyperpolarizing currents generated a slowly-rising voltage sag, and a post-hyperpolarization rebound. The amplitudes of both the sag voltage and the depolarizing rebound were dependent upon the strength of the hyperpolarizing current. The voltage sag showed a definite threshold and was non-inactivating. The voltage sag and rebound depolarization evoked by hyperpolarization were blocked by the presence of 5–10 mM Cs²⁺ ions, 10 mM tetraethyl ammonium chloride, and 10 mM cobalt chloride in the bathing medium, but not by the drug ZD 7288. Cs⁺ ions in normal saline in some cells caused a slight increase in mean resting potential and a reduction in spontaneous burst frequency. Many of the neurons expressing the hyperpolarization-activated inward potassium current also provided evidence for the presence of the transient potassium current I_A, which was inferred from experimental observations of an increased latency of post-hyperpolarization response to a depolarizing step, compared to the response latency to the depolarization alone. The latency increase was reduced in the presence of 4-aminopyridine (4-AP), a specific blocker of I_A. The presence of 4-AP in normal saline also induced spontaneous bursting in parasol cells. It is conjectured that, under normal physiological conditions, these two potassium currents help to regulate burst generation in parasol cells, respectively, by helping to maintain the resting membrane potential near a threshold level for burst generation, and by regulating the rate of rise of membrane depolarizing events leading to burst generation. The presence of post-burst hyperpolarization may depend upon I_A channels in parasol cells.     

Interpretation of the Repetitive Firing of Nerve Cells

Eccentric cells of Limulus respond with repetitive firing to sustained depolarizing currents. Following stimulation with a step of current, latency is shorter than first interval and later intervals increase progressively. A shock of intensity twice threshold can evoke firing 25 msec. after an impulse. But in the same cell, a current step twice rheobase evokes a second impulse more than 50 msec. after the first, and current intensity must be raised to over five times rheobase to obtain a first interval of about 25 msec. Repetitive firing was evoked by means of trains of shocks. With stimuli of moderate intensity, firing was evoked by only some of the shocks and intervals between successive impulses increased with time. This is ascribed to accumulation of refractoriness with successive impulses. Higher frequencies of firing are obtained with shocks of intensity n x threshold than with constant currents of intensity n x rheobase. It is concluded that prolonged currents depress the processes leading to excitation and that (in the cells studied) repetitive firing is controlled both by the after-effects of firing (refractoriness) and by the depressant effects of sustained stimuli (accommodation). Development of subthreshold "graded activity" is an important process leading to excitation of eccentric cells, but is not the principal factor determining frequency of firing in response to constant currents.     

Modeling Hermissenda: I. Differential contributions of I A and I C to type-B cell plasticity

We developed a multicompartmental Hodgkin-Huxley model of the Hermissenda type-B photoreceptor and used it to address the relative contributions of reductions of two K⁺ currents, I _a and I _C, to changes in cellular excitability and synaptic strength that occur in these cells after associative learning. We found that reductions of g_C, the peak conductance of I _C, substantially increased the firing frequency of the type-B cell during the plateau phase of a simulated light response, whereas reductions of g_A had only a modest contribution to the plateau frequency. This can be understood at least in part by the contributions of these currents to the light-induced (nonspiking) generator potential, the plateau of which was enhanced by g_C reductions, but not by g_A reductions. In contrast, however, reductions of g_A broadened the type-B cell action potential, increased Ca²⁺ influx, and increased the size of the postsynaptic potential produced in a type-A cell, whereas similar reductions of g_C had only negligible contributions to these measures. These results suggest that reductions of I _A and I _C play important but different roles in type-B cell plasticity.     

Contribution of slowly inactivating potassium current to delayed firing of action potentials in NG108-15 neuronal cells: experimental and theoretical studies

The properties of slowly inactivating delayed-rectifier K⁺ current (I_Kdr) were investigated in NG108-15 neuronal cells differentiated with long-term exposure to dibutyryl cyclic AMP. Slowly inactivating I_Kdr could be elicited by prolonged depolarizations from −50 to +50 mV. These outward K⁺ currents were found to decay at potentials above −20 mV, and the decay became faster with greater depolarization. Cell exposure to aconitine resulted in the reduction of I_Kdr amplitude along with an accelerated decay of current inactivation. Under current-clamp recordings, a delay in the initiation of action potentials (APs) in response to prolonged current stimuli was observed in these cells. Application of aconitine shortened the AP initiation in combination with an increase in both width of spike discharge and firing frequency. The computer model, in which state-dependent inactivation of I_Kdr was incorporated, was also implemented to predict the firing behavior present in NG108-15 cells. As the inactivation rate constant of I_Kdr was elevated, the firing frequency was progressively increased along with a shortening of the latency for AP appearance. Our theoretical work and the experimental results led us to propose a pivotal role of slowly inactivating I_Kdr in delayed firing of APs in NG108-15 cells. The results also suggest that aconitine modulation of I_Kdr gating is an important molecular mechanism through which it can contribute to neuronal firing.