Period doubling of calcium spike firing in a model of a Purkinje cell dendrite

Recordings from cerebellar Purkinje cell dendrites have revealed that in response to sustained current injection, the cell firing pattern can move from tonic firing of Ca²⁺ spikes to doublet firing and even to quadruplet firing or more complex firing. These firing patterns are not modified substantially if Na⁺ currents are blocked. We show that the experimental results can be viewed as a slow transition of the neuronal dynamics through a period-doubling bifurcation. To further support this conclusion and to understand the underlying mechanism that leads to doublet firing, we develop and study a simple, one-compartment model of Purkinje cell dendrite. The neuron can also exhibit quadruplet and chaotic firing patterns that are similar to the firing patterns that some of the Purkinje cells exhibit experimentally. The effects of parameters such as temperature, applied current, and potassium reversal potential in the model resemble their effects in experiments. The model dynamics involve three time scales. Ca²⁺- dependent K⁺ currents, with intermediate time scales, are responsible for the appearance of doublet firing, whereas a very slow hyperpolarizing current transfers the neuron from tonic to doublet firing. We use the fast-slow analysis to separate the effects of the three time scales. Fast-slow analysis of the neuronal dynamics, with the activation variable of the very slow, hyperpolarizing current considered as a parameter, reveals that the transitions occurs via a cascade of period-doubling bifurcations of the fast and intermediate subsystem as this slow variable increases. We carry out another analysis, with the Ca²⁺ concentration considered as a parameter, to investigate the conditions for the generation of doublet firing in systems with one effective variable with intermediate time scale, in which the rest state of the fast subsystem is terminated by a saddle-node bifurcation. We find that the scenario of period doubling in these systems can occur only if (1) the time scale of the intermediate variable (here, the decay rate of the calcium concentration) is slow enough in comparison with the interspike interval of the tonic firing at the transition but is not too slow and (2) there is a bistability of the fast subsystem of the spike-generating variables.     

Mathematical Model of Bursting in Dissociated Purkinje Neurons

In vitro, Purkinje cell behaviour is sometimes studied in a dissociated soma preparation in which the dendritic projection has been cleaved. A fraction of these dissociated somas spontaneously burst. The mechanism of this bursting is incompletely understood. We have constructed a biophysical Purkinje soma model, guided and constrained by experimental reports in the literature, that can replicate the somatically driven bursting pattern and which hypothesises Persistent Na⁺ current (I_NaP) to be its burst initiator and SK K⁺ current (I_SK) to be its burst terminator.     

The Output Signal of Purkinje Cells of the Cerebellum and Circadian Rhythmicity

Measurement of clock gene expression has recently provided evidence that the cerebellum, like the master clock in the SCN, contains a circadian oscillator. The cerebellar oscillator is involved in anticipation of mealtime and possibly resides in Purkinje cells. However, the rhythmic gene expression is likely transduced into a circadian cerebellar output signal to exert an effective control of neuronal brain circuits that are responsible for feeding behavior. Using electrophysiological recordings from acute and organotypic cerebellar slices, we tested the hypothesis whether Purkinje cells transmit a circadian modulated signal to their targets in the brain. Extracellular recordings from brain slices revealed the typical discharge pattern previously described in vivo in single cell recordings showing basically a tonic or a trimodal-like firing pattern. However, in acute sagittal cerebellar slices the average spike rate of randomly selected Purkinje cells did not exhibit significant circadian variations, irrespective of their specific firing pattern. Also, frequency and amplitude of spontaneous inhibitory postsynaptic currents and the amplitude of GABA- and glutamate-evoked currents did not vary with circadian time. Long-term recordings using multielectrode arrays (MEA) allowed to monitor neuronal activity at multiple sites in organotypic cerebellar slices for several days to weeks. With this recording technique we observed oscillations of the firing rate of cerebellar neurons, presumably of Purkinje cells, with a period of about 24 hours which were stable for periods up to three days. The daily renewal of culture medium could induce circadian oscillations of the firing rate of Purkinje cells, a feature that is compatible with the behavior of slave oscillators. However, from the present results it appears that the circadian expression of cerebellar clock genes exerts only a weak influence on the electrical output of cerebellar neurons.     

Dynamic excitation states and firing patterns are controlled by sodium channel kinetics in myenteric neurons: a simulation study

Enteric neurons located in the gastro-intestinal tract are of particular importance to control digestive functions such as motility and secretion. In our recent publication, we showed that mouse myenteric neurons exhibit 2 types of tetrodotoxin-resistant Na⁺ currents: a fast inactivating Na⁺ current produced by Nav1.5 channels, present in nearly all myenteric neurons, and a persistent Na⁺ current attributed to Nav1.9 channels, restricted to the intrinsic primary afferent neurons (IPANs). By combination of experimental recording and computer simulation we found that Nav1.5 contributed to the upstroke velocity of action potentials (APs), whereas Nav1.9 opposed AP repolarization. Here, we detailed the Na⁺, Ca²⁺ and K⁺ currents used in our computational model of IPAN. We refined the prototype cell to reproduce the sustained firing pattern recorded in situ. As shown in experimental conditions we demonstrated that Nav1.9 channels critically determine the up-state life-time and thus, are essential to sustain tonic firing.     

Dynamic excitation states and firing patterns are controlled by sodium channel kinetics in myenteric neurons: a simulation study

Enteric neurons located in the gastro-intestinal tract are of particular importance to control digestive functions such as motility and secretion. In our recent publication, we showed that mouse myenteric neurons exhibit 2 types of tetrodotoxin-resistant Na⁺ currents: a fast inactivating Na⁺ current produced by Nav1.5 channels, present in nearly all myenteric neurons, and a persistent Na⁺ current attributed to Nav1.9 channels, restricted to the intrinsic primary afferent neurons (IPANs). By combination of experimental recording and computer simulation we found that Nav1.5 contributed to the upstroke velocity of action potentials (APs), whereas Nav1.9 opposed AP repolarization. Here, we detailed the Na⁺, Ca²⁺ and K⁺ currents used in our computational model of IPAN. We refined the prototype cell to reproduce the sustained firing pattern recorded in situ. As shown in experimental conditions we demonstrated that Nav1.9 channels critically determine the up-state life-time and thus, are essential to sustain tonic firing.     

Inward-directed current generated by the Na+,K+ pump in Na+- and K+-free medium

In Na⁺- and K⁺-free solution, an inward-directed current can be detected in Xenopus oocytes, which is inhibited by cardic glycosides and activated by ATP. Therefore, it is assumed to be generated by the Na⁺, K⁺ pump. At negative membrane potentials, the pump current increases with more negative potentials and with increasing [H⁺] in the external medium. This current is not observed when Mg²⁺ instead of Ba²⁺ is the only divalent cation present in the bath medium, and it does not depend on whether Na⁺ or K⁺ is present internally. At 5 to 10 mM Na⁺ externally, maximum pump-generated current is obtained while no current can be detected in presence of physiological [Na⁺]. It is suggested that in low-Na⁺ and K⁺-free medium the Na⁺, K⁺ pump molecule can either form a conductive pathway that is permeable to Ba²⁺ or protons or operate in its conventional transport mode accepting Ba²⁺ as a K⁺ congener. A reversed pump mode or an electrogenic uncoupled Na⁺-efflux mode is excluded.     

Pacemaking mechanism of the afterdischarge of the ovulation hormone-producing caudo-dorsal cells in the gastropod mollusc Lymnaea stagnalis

The ovulation hormone-producing caudo-dorsal cells (CDC) of Lymnaea stagnalis have three states of excitability (active, inhibited, and resting), which are related to the egg-laying cycle. Active state CDC produce a firing pattern of prolonged spiking activity (1 spike/2 s), which in the animal occurs shortly before egg laying. In preparations it is evoked as an afterdischarge upon repetitive stimulation of CDC. The afterdischarge is not synaptically driven, but rests on a pacemaking mechanism. CDC are silent in the inhibited and resting states, which follow egg laying. In these states the membrane potential is mainly dependent on [K⁺]₀. In the active state the ratio of the K⁺, Na⁺, and Ca²⁺ permeabilities has changed considerably, probably resulting from an increased permeability to Na⁺ and Ca²⁺. The firing rate in the afterdischarge is dependent on the membrane potential, which is confirmed experimentally by varying [K⁺]₀.[Na⁺]₀ and [Ca²⁺]₀ directly influence the firing rate. Firing stops in Na⁺-free saline, but is enhanced by Ca²⁺-free or high-Mg²⁺ saline. TTX does not affect firing. Relatively high concentrations of Co²⁺ and La³⁺ (2 × 10^?3M) strongly inhibit CDC. Regular firing can be changed into bursting by various means, such as high K⁺ or addition of 1 mM Ba²⁺. Bursting normally occurs at the beginning of the afterdischarge. Postburst hyperpolarizations are reduced in Ca²⁺-free saline and by low Co²⁺ (10^?4-5 10^?4M). Active CDC are driven by a pacemaking mechanism constituted by a voltage-dependent Na⁺/Ca²⁺ channel and a Ca²⁺-dependent K⁺ channel, thus resembling that of bursting pacemakers. The pacemaking mechanism is inactive in the resting and inhibited state.     

The influence of potassium concentration on epileptic seizures in a coupled neuronal model in the hippocampus

Experiments on hippocampal slices have recorded that a novel pattern of epileptic seizures with alternating excitatory and inhibitory activities in the CA1 region can be induced by an elevated potassium ion (K⁺) concentration in the extracellular space between neurons and astrocytes (ECS-NA). To explore the intrinsic effects of the factors (such as glial K⁺ uptake, Na⁺–K⁺-ATPase, the K⁺ concentration of the bath solution, and K⁺ lateral diffusion) influencing K⁺ concentration in the ECS-NA on the epileptic seizures recorded in previous experiments, we present a coupled model composed of excitatory and inhibitory neurons and glia in the CA1 region. Bifurcation diagrams showing the glial K⁺ uptake strength with either the Na⁺–K⁺-ATPase pump strength or the bath solution K⁺ concentration are obtained for neural epileptic seizures. The K⁺ lateral diffusion leads to epileptic seizure in neurons only when the synaptic conductance values of the excitatory and inhibitory neurons are within an appropriate range. Finally, we propose an energy factor to measure the metabolic demand during neuron firing, and the results show that different energy demands for the normal discharges and the pathological epileptic seizures of the coupled neurons.     

Seizure-like afterdischarges simulated in a model neuron

To explore non-synaptic mechanisms in paroxysmal discharges, we used a computer model of a simplified hippocampal pyramidal cell, surrounded by interstitial space and a “glial-endothelial” buffer system. Ion channels for Na⁺, K⁺, Ca²⁺ and Cl⁻ _, ion antiport 3Na/Ca, and “active” ion pumps were represented in the neuron membrane. The glia had “leak” conductances and an ion pump. Fluxes, concentration changes and cell swelling were computed. The neuron was stimulated by injecting current. Afterdischarge (AD) followed stimulation if depolarization due to rising interstitial K⁺ concentration ([K⁺]_o) activated persistent Na⁺ current (I _Na,P). AD was either simple or self-regenerating; either regular (tonic) or burst-type (clonic); and always self-limiting. Self-regenerating AD required sufficient I _Na,P to ensure re-excitation. Burst firing depended on activation of dendritic Ca²⁺ currents and Ca-dependent K⁺ current. Varying glial buffer function influenced [K⁺]_o accumulation and afterdischarge duration. Variations in Na⁺ and K⁺ currents influenced the threshold and the duration of AD. The data show that high [K⁺]_o and intrinsic membrane currents can produce the feedback of self-regenerating afterdischarges without synaptic input. The simulated discharge resembles neuron behavior during paroxysmal firing in living brain tissue. Action Editor: David Terman     

Study on the dehydrating effect of the red cell Na+/K+-pump in nystatin-treated cells with varying Na+ and water contents

Using the antibiotic Nystatin, we have developed a systematic method for the preparation of red blood cells with independently selected levels of intracellular Na⁺ concentrations and water content. Such cells provided an experimental model to study the effect of Na⁺/K⁺ pump stimulation on red cell water content. Even in initially dehydrated cells, stimulation of the Na⁺/K⁺ pump by elevated intracellular Na⁺ caused subsequent further loss of cell water. Cell water loss was reflected in decreased monovalent cation content per unit mass of hemoglobin and by a shift in the density distribution of the cell populations to higher densities on discontinuous Stractan gradients. We conclude that the 3 Na_out⁺ : 2 K_in⁺ stoichiometry of the Na⁺/K⁺ pump results in a net desalting effect with increased pump activity. Under the conditions of these experiments, the cell appears to have no effective mechanism to compensate for a net loss of ions and water.     

The role of extracellular potassium dynamics in the different stages of ictal bursting and spreading depression: A computational study

Experimental evidences point out the participation of nonsynaptic mechanisms (e.g., fluctuations in extracellular ions) in epileptiform bursting and spreading depression (SD). During these abnormal oscillatory patterns, it is observed an increase of extracellular potassium concentration [K⁺]_o and a decrease of extracellular calcium concentration [Ca²⁺]_o which raises the neuronal excitability. However, whether the high [K⁺]_o triggers and propagates these abnormal neuronal activities or plays a secondary role into this process is unclear. To better understand the influence of extracellular potassium dynamics in these oscillatory patterns, the experimental conditions of high [K⁺]_o and zero [Ca²⁺]_o were replicated in an extended Golomb model where we added important regulatory mechanisms of ion concentration as Na⁺-K⁺ pump, ion diffusion and glial buffering. Within these conditions, simulations of the cell model exhibit seizure-like discharges (ictal bursting). The SD was elicited by the interruption of the Na⁺−K⁺ pump activity, mimicking the effect of cellular hypoxia (an experimental protocol to elicit SD, the hypoxia-induced SD). We used the bifurcation theory and the fast-slow method to analyze the interference of K⁺ dynamics in the cellular excitability. This analysis indicates that the system loses its stability at a high [K⁺]_o, transiting to an elevated state of neuronal excitability. Effects of high [K⁺]_o are observed in different stages of ictal bursting and SD. In the initial stage, the increase of [K⁺]_o creates favorable conditions to trigger both oscillatory patterns. During the neuronal activity, a continuous growth of [K⁺]_o by outward K⁺ flow depresses K⁺ currents in a positive feedback way. At the last stage, due to the depression of K⁺ currents, the Na⁺-K⁺ pump is the main mechanism in the end of neuronal activity. Thus, this work suggests that [K⁺]_o dynamics may play a fundamental role in these abnormal oscillatory patterns.     

Characterization of the cardiac Na/K pump by development of a comprehensive and mechanistic model

A large amount of experimental data on the characteristics of the cardiac Na⁺/K⁺ pump have been accumulated, but it remains difficult to predict the quantitative contribution of the pump in an intact cell because most measurements have been made under non-physiological conditions. To extrapolate the experimental findings to intact cells, we have developed a comprehensive Na⁺/K⁺ pump model based on the thermodynamic framework (Smith and Crampin, 2004) of the Post-Albers reaction cycle combined with access channel mechanisms. The new model explains a variety of experimental results for the Na⁺/K⁺ pump current (I_NaK), including the dependency on the concentrations of Na⁺ and K⁺, the membrane potential and the free energy of ATP hydrolysis. The model demonstrates that both the apparent affinity and the slope of the substrate-I_NaK relationship measured experimentally are affected by the composition of ions in the extra- and intracellular solutions, indirectly through alteration in the probability distribution of individual enzyme intermediates. By considering the voltage dependence in the Na⁺- and K⁺-binding steps, the experimental voltage-I_NaK relationship could be reconstructed with application of experimental ionic compositions in the model, and the view of voltage-dependent K⁺ binding was supported. Re-evaluation of charge movements accompanying Na⁺ and K⁺ translocations gave a reasonable number for the site density of the Na⁺/K⁺ pump on the membrane. The new model is relevant for simulation of cellular functions under various interventions, such as depression of energy metabolism.     

On the Concept of Resting Potential—Pumping Ratio of the Na+/K+ Pump and Concentration Ratios of Potassium Ions Outside and Inside the Cell to Sodium Ions Inside and Outside the Cell

In animal cells, the resting potential is established by the concentration gradients of sodium and potassium ions and the different permeabilities of the cell membrane to them. The large concentration gradients of sodium and potassium ions are maintained by the Na⁺/K⁺ pump. Under physiological conditions, the pump transports three sodium ions out of and two potassium ions into the cell per ATP hydrolyzed. However, unlike other primary or secondary active transporters, the Na⁺/K⁺ pump does not work at the equilibrium state, so the pumping ratio is not a thermodynamic property of the pump. In this article, I propose a dipole-charging model of the Na⁺/K⁺ pump to prove that the three Na⁺ to two K⁺ pumping ratio of the Na⁺/K⁺ pump is determined by the ratio of the ionic mobilities of potassium to sodium ions, which is to ensure the time constant τ and the τ-dependent processes, such as the normal working state of the Na⁺/K⁺ pump and the propagation of an action potential. Further, the concentration ratios of potassium ions outside and inside the cell to sodium ions inside and outside the cell are 0.3027 and 0.9788, respectively, and the sum of the potassium and sodium equilibrium potentials is ?30.3 mV. A comparative study on these constants is made for some marine, freshwater and terrestrial animals. These findings suggest that the pumping ratio of the Na⁺/K⁺ pump and the ion concentration ratios play a role in the evolution of animal cells.     

Na+/K+-ATPase Inhibition Partially Mimics the Ethanol-Induced Increase of the Golgi Cell-Dependent Component of the Tonic GABAergic Current in Rat Cerebellar Granule Cells

Cerebellar granule cells (CGNs) are one of many neurons that express phasic and tonic GABAergic conductances. Although it is well established that Golgi cells (GoCs) mediate phasic GABAergic currents in CGNs, their role in mediating tonic currents in CGNs (CGN-I_tonic) is controversial. Earlier studies suggested that GoCs mediate a component of CGN-I_tonic that is present only in preparations from immature rodents. However, more recent studies have detected a GoC-dependent component of CGN-I_tonic in preparations of mature rodents. In addition, acute exposure to ethanol was shown to potentiate the GoC component of CGN-I_tonic and to induce a parallel increase in spontaneous inhibitory postsynaptic current frequency at CGNs. Here, we tested the hypothesis that these effects of ethanol on GABAergic transmission in CGNs are mediated by inhibition of the Na⁺/K⁺-ATPase. We used whole-cell patch-clamp electrophysiology techniques in cerebellar slices of male rats (postnatal day 23–30). Under these conditions, we reliably detected a GoC-dependent component of CGN-I_tonic that could be blocked with tetrodotoxin. Further analysis revealed a positive correlation between basal sIPSC frequency and the magnitude of the GoC-dependent component of CGN-I_tonic. Inhibition of the Na⁺/K⁺-ATPase with a submaximal concentration of ouabain partially mimicked the ethanol-induced potentiation of both phasic and tonic GABAergic currents in CGNs. Modeling studies suggest that selective inhibition of the Na⁺/K⁺-ATPase in GoCs can, in part, explain these effects of ethanol. These findings establish a novel mechanism of action of ethanol on GABAergic transmission in the central nervous system.     

Evidence for frequency-dependent extracellular impedance from the transfer function between extracellular and intracellular potentials

Dopaminergic (DA) neurons of the mammalian midbrain exhibit unusually low firing frequencies in vitro. Furthermore, injection of depolarizing current induces depolarization block before high frequencies are achieved. The maximum steady and transient rates are about 10 and 20 Hz, respectively, despite the ability of these neurons to generate bursts at higher frequencies in vivo. We use a three-compartment model calibrated to reproduce DA neuron responses to several pharmacological manipulations to uncover mechanisms of frequency limitation. The model exhibits a slow oscillatory potential (SOP) dependent on the interplay between the L-type Ca²⁺ current and the small conductance K⁺ (SK) current that is unmasked by fast Na⁺ current block. Contrary to previous theoretical work, the SOP does not pace the steady spiking frequency in our model. The main currents that determine the spontaneous firing frequency are the subthreshold L-type Ca²⁺ and the A-type K⁺ currents. The model identifies the channel densities for the fast Na⁺ and the delayed rectifier K⁺ currents as critical parameters limiting the maximal steady frequency evoked by a depolarizing pulse. We hypothesize that the low maximal steady frequencies result from a low safety factor for action potential generation. In the model, the rate of Ca²⁺ accumulation in the distal dendrites controls the transient initial frequency in response to a depolarizing pulse. Similar results are obtained when the same model parameters are used in a multi-compartmental model with a realistic reconstructed morphology, indicating that the salient contributions of the dendritic architecture have been captured by the simpler model.     

Roles of electrogenic Na+ pump and K+ conductance in the slow inhibitory postsynaptic potential of bullfrog sympathetic ganglion cells

The slow IPSP recorded from bullfrog sympathetic ganglion cells in the Ringer solution consists of two different potential components, namely ouabain-sensitive and ouabain-insensitive components. The present experimental analyses on these two potential components suggest that the former component is associated with an electrogenic Na⁺ pump while the latter with an increase of K⁺-conductance. The slow IPSP recorded in K⁺-free solution is clearly mixed with a new potential component, which is not seen in the Ringer solution and differs from the usual slow IPSP. These results do not support the concept that the slow IPSP consists of the potential component associated with a fall of Na⁺ conductance.     

Glutathionylation-Dependence of Na+-K+-Pump Currents Can Mimic Reduced Subsarcolemmal Na+ Diffusion

The existence of a subsarcolemmal space with restricted diffusion for Na⁺ in cardiac myocytes has been inferred from a transient peak electrogenic Na⁺-K⁺ pump current beyond steady state on reexposure of myocytes to K⁺ after a period of exposure to K⁺-free extracellular solution. The transient peak current is attributed to enhanced electrogenic pumping of Na⁺ that accumulated in the diffusion-restricted space during pump inhibition in K⁺-free extracellular solution. However, there are no known physical barriers that account for such restricted Na⁺ diffusion, and we examined if changes of activity of the Na⁺-K⁺ pump itself cause the transient peak current. Reexposure to K⁺ reproduced a transient current beyond steady state in voltage-clamped ventricular myocytes as reported by others. Persistence of it when the Na⁺ concentration in patch pipette solutions perfusing the intracellular compartment was high and elimination of it with K⁺-free pipette solution could not be reconciled with restricted subsarcolemmal Na⁺ diffusion. The pattern of the transient current early after pump activation was dependent on transmembrane Na⁺- and K⁺ concentration gradients suggesting the currents were related to the conformational poise imposed on the pump. We examined if the currents might be accounted for by changes in glutathionylation of the β₁ Na⁺-K⁺ pump subunit, a reversible oxidative modification that inhibits the pump. Susceptibility of the β₁ subunit to glutathionylation depends on the conformational poise of the Na⁺-K⁺ pump, and glutathionylation with the pump stabilized in conformations equivalent to those expected to be imposed on voltage-clamped myocytes supported this hypothesis. So did elimination of the transient K⁺-induced peak Na⁺-K⁺ pump current when we included glutaredoxin 1 in patch pipette solutions to reverse glutathionylation. We conclude that transient K⁺-induced peak Na⁺-K⁺ pump current reflects the effect of conformation-dependent β₁ pump subunit glutathionylation, not restricted subsarcolemmal diffusion of Na⁺.     

Na+/ K+-pump activity in photoreceptors of the blowfly Calliphora : a model analysis based on membrane potential measurements

Na⁺/K⁺-pump activity and intracellular Na⁺ and K⁺ concentration changes in blowfly photoreceptors are derived from intracellular potential measurements in␣vivo with a model based on the Goldman-Hodgkin-Katz theory for membrane currents. The relation between the intracellular Na⁺ concentration and the pump activity appears to follow a Hill function with a Hill coefficient of 1 and a maximal possible Na⁺ current due to pump activity of about −4 nA. The developed photoreceptor model incorporates the slow and fast voltage-dependent K⁺ channels of the blowfly photoreceptor of which the properties were taken from the literature. Accepted: 5 August 1996     

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     

Functional Interaction between the Scaffold Protein Kidins220/ARMS and Neuronal Voltage-Gated Na+ Channels

Kidins220 (kinase D-interacting substrate of 220 kDa)/ankyrin repeat-rich membrane spanning (ARMS) acts as a signaling platform at the plasma membrane and is implicated in a multitude of neuronal functions, including the control of neuronal activity. Here, we used the Kidins220^−/− mouse model to study the effects of Kidins220 ablation on neuronal excitability. Multielectrode array recordings showed reduced evoked spiking activity in Kidins220^−/− hippocampal networks, which was compatible with the increased excitability of GABAergic neurons determined by current-clamp recordings. Spike waveform analysis further indicated an increased sodium conductance in this neuronal subpopulation. Kidins220 association with brain voltage-gated sodium channels was shown by co-immunoprecipitation experiments and Na⁺ current recordings in transfected HEK293 cells, which revealed dramatic alterations of kinetics and voltage dependence. Finally, an in silico interneuronal model incorporating the Kidins220-induced Na⁺ current alterations reproduced the firing phenotype observed in Kidins220^−/− neurons. These results identify Kidins220 as a novel modulator of Na_v channel activity, broadening our understanding of the molecular mechanisms regulating network excitability.