Low-threshold Potassium Currents Research Articles

Distribution of Kv1‐like potassium channels in the electromotor and electrosensory systems of the weakly electric fish Apteronotus leptorhynchus

The electromotor and electrosensory systems of the weakly electric fish Apteronotus leptorhynchus are model systems for studying mechanisms of high-frequency motor pattern generation and sensory processing. Voltage-dependent ionic currents, including low-threshold potassium currents, influence excitability of neurons in these circuits and thereby regulate motor output and sensory filtering. Although Kv1-like potassium channels are likely to carry low-threshold potassium currents in electromotor and electrosensory neurons, the distribution of Kv1 alpha subunits in A. leptorhynchus is unknown. In this study, we used immunohistochemistry with six different antibodies raised against specific mammalian Kv1 alpha subunits (Kv1.1-Kv1.6) to characterize the distribution of Kv1-like channels in electromotor and electrosensory structures. Each Kv1 antibody labeled a distinct subset of neurons, fibers, and/or dendrites in electromotor and electrosensory nuclei. Kv1-like immunoreactivity in the electrosensory lateral line lobe (ELL) and pacemaker nucleus are particularly relevant in light of previous studies suggesting that potassium currents carried by Kv1 channels regulate neuronal excitability in these regions. Immunoreactivity of pyramidal cells in the ELL with several Kv1 antibodies is consistent with Kv1 channels carrying low-threshold outward currents that regulate spike waveform in these cells (Fernandez et al., J Neurosci 2005;25:363-371). Similarly, Kv1-like immunoreactivity in the pacemaker nucleus is consistent with a role of Kv1 channels in spontaneous high-frequency firing in pacemaker neurons. Robust Kv1-like immunoreactivity in several other structures, including the dorsal torus semicircularis, tuberous electroreceptors, and the electric organ, indicates that Kv1 channels are broadly expressed and are likely to contribute significantly to generating the electric organ discharge and processing electrosensory inputs.

Serotonergic modulation of persistent sodium currents and membrane excitability via cyclic AMP‐protein kinase A cascade in mesencephalic V neurons

In rat mesencephalic trigeminal (Mes V) neurons, persistent sodium currents in conjunction with low-threshold potassium currents are critical for generation of subthreshold membrane oscillations and onset of burst behavior. Here we demonstrate that the cAMP/protein kinase A (PKA) signaling pathway modulates persistent sodium currents. In particular, we show that elevation of cAMP suppresses a low-threshold I(NaP) via a PKA intracellular pathway. Bath application of forskolin (20 microM), a stimulant for the production of cAMP, reduced the peak I(NaP). 1,9-Dideoxy-forskolin (20 microM), an inactive form of forskolin, produced minimal effects on I(NaP), and the membrane-permeable cAMP analogue 8-bromo-cAMP (500 microM) mimicked the effect of forskolin. Additionally, preapplication of H89 (2 microM), a specific PKA inhibitor, suppressed the effect of forskolin, suggesting the involvement of the cAMP/PKA intracellular signaling pathway in this modulation. 5-HT receptor stimulation (20 microM) also mimicked the modulation of I(NaP) by forskolin via the cAMP/PKA-dependent signaling pathway. Current clamp analysis demonstrated that voltage-dependent membrane resonance in response to a ZAP input current at depolarized holding potentials (approximately -50 mV) was specifically suppressed by forskolin or 5-HT. Moreover, drug application enhanced frequency adaptation in response to a 1-sec current pulse. These results indicate that modulation of persistent sodium currents by a cAMP/PKA pathway can significantly alter the membrane excitability and discharge characteristics of Mes V neurons.

Distribution and function of potassium channels in the electrosensory lateral line lobe of weakly electric apteronotid fish

Potassium channels are one of the fundamental requirements for the generation of action potentials in the nervous system, and their characteristics shape the output of neurons in response to synaptic input. We review here the distribution and function of a high-threshold potassium channel (Kv3.3) in the electrosensory lateral line lobe of the weakly electric fish Apteronotus leptorhynchus, with particular focus on the pyramidal cells in this brain structure. These cells contain both high-threshold Kv3.3 channels, as well as low-threshold potassium channels of unknown molecular identity. Kv3.3 potassium channels regulate burst discharge in pyramidal cells and enable sustained high frequency firing through their ability to reduce an accumulation of low-threshold potassium current.

Hyperpolarization‐activated (Ih) currents in auditory brainstem neurons of normal and congenitally deaf mice

We have investigated the membrane properties of brainstem auditory neurons in a mouse model of congenital deafness (dn/dn). Whole-cell recordings were made from visualized neurons in slices of the medial nucleus of the trapezoid body (MNTB) and anteroventral cochlear nucleus (AVCN). We have recently demonstrated that MNTB neurons in deaf mice are more excitable than in normal mice, due in part to a reduced expression of low-threshold potassium currents. In this study, we have examined the contribution of hyperpolarization-activated (Ih) channels to the membrane properties of MNTB and AVCN neurons. Our results show that Ih is larger in MNTB neurons from deaf mice than in normal mice. In contrast, no significant differences were found in Ih or excitability between AVCN bushy cells from dn/dn and normal mice. Experimental evidence and neuronal modelling suggests that, in the MNTB of normal mice, a small contribution of Ih helps to reduce temporal summation of synaptic potentials. A larger Ih in neurons from deaf mice has a much greater effect in reducing temporal summation of synaptic potentials, counteracting to some extent the greater excitability of these cells. Our results provide further insight into the role of activity during development in regulating the membrane and firing properties of central neurons.

Kv1 currents mediate a gradient of principal neuron excitability across the tonotopic axis in the rat lateral superior olive.

Principal neurons of the lateral superior olive (LSO) detect interaural intensity differences by integration of excitatory projections from ipsilateral bushy cells and inhibitory inputs from the medial nucleus of the trapezoid body. The intrinsic membrane currents active around firing threshold will form an important component of this binaural computation. Whole cell patch recording in an in vitro brain slice preparation was employed to study conductances regulating action potential (AP) firing in principal neurons. Current-clamp recordings from different neurons showed two types of firing pattern on depolarization, one group fired only a single initial AP and had low input resistance while the second group fired multiple APs and had a high input resistance. Under voltage-clamp, single-spiking neurons showed significantly higher levels of a dendrotoxin-sensitive, low threshold potassium current (ILT). Block of ILT by dendrotoxin-I allowed single-spiking cells to fire multiple APs and indicated that this current was mediated by Kv1 channels. Both neuronal types were morphologically similar and possessed similar amounts of the hyperpolarization-activated nonspecific cation conductance (Ih). However, single-spiking cells predominated in the lateral limb of the LSO (receiving low frequency sound inputs) while multiple-firing cells dominated the medial limb. This functional gradient was mirrored by a medio-lateral distribution of Kv1.1 immunolabelling. We conclude that Kv1 channels underlie the gradient of LSO principal neuron firing properties. The properties of single-spiking neurons would render them particularly suited to preserving timing information.

Functional Specialization of Male and Female Vocal Motoneurons

Vocal behaviors of African clawed frogs (Xenopus laevis) are produced by a single pair of muscles. This simplification, relative to other vertebrates, allows us to more easily determine how CNS motor pathways function to produce sex-specific songs. We describe here certain sexually differentiated properties of vocal motoneurons that are matched to male and female vocal demands. Both active and passive membrane properties differ between the sexes. Male motoneurons have lower input resistances and larger membrane capacitances than female motoneurons. Two distinct firing patterns are found, in different proportions, in males and females. The strongly adapting neurons that predominate in males initiate spikes at short, reliable latencies, whereas the weakly adapting motoneurons characteristic of females translate graded levels of depolarization into different firing rates. Low-threshold potassium currents (IKL) predominate in males. Hyperpolarization-activated cationic currents (IH) are found almost exclusively in males. Modeling results indicate that sex-typical active and passive properties can account for the occurrence of strongly and weakly adapting spike trains in the sexes. In particular, IKL seem to play an important role in determining the firing patterns of neurons. We suggest that these physiological differences facilitate transformation of synaptic inputs into male- and female-specific outputs that generate sexually distinct songs in vivo.

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 neuron's 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 model's 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.

Expression of the Kv1.1 ion channel subunit in the auditory brainstem of the big brown bat, Eptesicus fuscus.

Voltage-gated potassium channels play an important role in shaping membrane properties that underlie neurons' discharge patterns and the ways in which they transform their input. In the auditory system, low threshold potassium currents such as those created by Kv1.1 subunits contribute to precise phaselocking and to transient onset responses that provide time markers for temporal features of sounds. The purpose of the present study was to compare information about the distribution of neurons expressing the KV 1.1 in the brainstem auditory nuclei with the distribution of neurons with known functional properties in the auditory system of the big brown bat, Eptesicus fuscus. We used immunocytochemistry and light microscopy to look at the distribution of Kv1.1 subunits in the brainstem auditory nuclei. There was prominent expression in cell types known to contain high levels of Kv1.1 in other species and known to respond to auditory signals with high temporal precision. These included octopus cells and spherical bushy cells of the cochlear nucleus and principal neurons of the medial nucleus of the trapezoid body. In addition, we found high levels of Kv1.1 in neurons of the columnar subdivision of the ventral nucleus of the lateral lemniscus and in ventral periolivary cell groups. Neurons with high levels of Kv1.1 were differentially distributed in the intermediate nucleus of the lateral lemniscus and in the inferior colliculus, suggesting that these structures contain functionally distinct cell populations, some of which may be involved in high-precision temporal processing.

Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1

Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1

Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1.

A low voltage-activated potassium current, IKL, is found in auditory neuron types that have low excitability and precisely preserve the temporal pattern of activity present in their presynaptic inputs. The gene Kcna1 codes for Kv1.1 potassium channel subunits, which combine in expression systems to produce channel tetramers with properties similar to those of IKL, including sensitivity to dendrotoxin (DTX). Kv1.1 is strongly expressed in neurons with IKL, including auditory neurons of the medial nucleus of the trapezoid body (MNTB). We therefore decided to investigate how the absence of Kv1.1 affected channel properties and function in MNTB neurons from mice lacking Kcna1. We used the whole cell version of the patch clamp technique to record from MNTB neurons in brainstem slices from Kcna1-null (-/-) mice and their wild-type (+/+) and heterozygous (+/-) littermates. There was an IKL in voltage-clamped -/- MNTB neurons, but it was about half the amplitude of the IKL in +/+ neurons, with otherwise similar properties. Consistent with this, -/- MNTB neurons were more excitable than their +/+ counterparts; they fired more than twice as many action potentials (APs) during current steps, and the threshold current amplitude required to generate an AP was roughly halved. +/- MNTB neurons had excitability and IKL amplitudes identical to the +/+ neurons. The IKL remaining in -/- neurons was blocked by DTX, suggesting the underlying channels contained subunits Kv1.2 and/or Kv1.6 (also DTX-sensitive). DTX increased excitability further in the already hyperexcitable -/- MNTB neurons, suggesting that -/- IKL limited excitability despite its reduced amplitude in the absence of Kv1.1 subunits.

Enhancement of Signal-to-Noise Ratio and Phase Locking for Small Inputs by a Low-Threshold Outward Current in Auditory Neurons

Neurons possess multiple voltage-dependent conductances specific for their function. To investigate how low-threshold outward currents improve the detection of small signals in a noisy background, we recorded from gerbil medial superior olivary (MSO) neurons in vitro. MSO neurons responded phasically, with a single spike to a step current injection. When bathed in dendrotoxin (DTX), most cells switched to tonic firing, suggesting that low-threshold potassium currents (I(KLT)) participated in shaping these phasic responses. Neurons 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"). DTX reduced the signal-to-noise ratio (SNR), defined as the ratio of probability to fire in response to the EPSG and the probability to fire spontaneously in response to noise. The reduction was mainly attributable to the increase of spontaneous firing in DTX. The spike-triggered reverse correlation indicated that, for spike generation, the neuron with I(KLT) required faster inward current transients. This narrow temporal integration window contributed to superior phase locking of firing to periodic stimuli before application of DTX. A computer model including Hodgkin-Huxley type conductances for spike generation and for I(KLT) (Rathouz and Trussell, 1998) showed similar response statistics. The dynamic low-threshold outward current increased SNR and the temporal precision of integration of weak subthreshold signals in auditory neurons by suppressing false positives.

Response of binaural neurons of dog superior olivary complex to dichotic tonal stimuli: some physiological mechanisms of sound localization.

Response of binaural neurons of dog superior olivary complex to dichotic tonal stimuli: some physiological mechanisms of sound localization.