Low-threshold Potassium Channels Research Articles

Auditory Brainstem Models: Adapting Cochlear Nuclei Improve Spatial Encoding by the Medial Superior Olive in Reverberation.

Listeners typically perceive a sound as originating from the direction of its source, even as direct sound is followed milliseconds later by reflected sound from multiple different directions. Early-arriving sound is emphasised in the ascending auditory pathway, including the medial superior olive (MSO) where binaural neurons encode the interaural-time-difference (ITD) cue for spatial location. Perceptually, weighting of ITD conveyed during rising sound energy is stronger at 600 Hz than at 200 Hz, consistent with the minimum stimulus rate for binaural adaptation, and with the longer reverberation times at 600 Hz, compared with 200 Hz, in many natural outdoor environments. Here, we computationally explore the combined efficacy of adaptation prior to the binaural encoding of ITD cues, and excitatory binaural coincidence detection within MSO neurons, in emphasising ITDs conveyed in early-arriving sound. With excitatory inputs from adapting, nonlinear model spherical bushy cells (SBCs) of the bilateral cochlear nuclei, a nonlinear model MSO neuron with low-threshold potassium channels reproduces the rate-dependent emphasis of rising vs. peak sound energy in ITD encoding; adaptation is equally effective in the model MSO. Maintaining adaptation in model SBCs, and adjusting membrane speed in model MSO neurons, 'left' and 'right' populations of computationally efficient, linear model SBCs and MSO neurons reproduce this stronger weighting of ITD conveyed during rising sound energy at 600 Hz compared to 200 Hz. This hemispheric population model demonstrates a link between strong weighting of spatial information during rising sound energy, and correct unambiguous lateralisation of a speech source in reverberation.

Non-synaptic Plasticity in Leech Touch Cells.

The role of Na+/K+-pumps in activity-dependent synaptic plasticity has been described in both vertebrates and invertebrates. Here, we provide evidence that the Na+/K+-pump is also involved in activity-dependent non-synaptic cellular plasticity in leech sensory neurons. We show that the resting membrane potential (RMP) of T cells hyperpolarizes in response to repeated somatic current injection, while at the same time their spike count (SC) and the input resistance (IR) increase. Our Hodgkin–Huxley-type neuron model, adjusted to physiological T cell properties, suggests that repetitive action potential discharges lead to increased Na+/K+-pump activity, which then hyperpolarizes the RMP. In consequence, a slow, non-inactivating current decreases, which is presumably mediated by voltage-dependent, low-threshold potassium channels. Closing of these putative M-type channels due to hyperpolarization of the resting potential increases the IR of the cell, leading to a larger number of spikes. By this mechanism, the response behavior switches from rapidly to slowly adapting spiking. These changes in spiking behavior also effect other T cells on the same side of the ganglion, which are connected via a combination of electrical and chemical synapses. An increased SC in the presynaptic T cell results in larger postsynaptic responses (PRs) in the other T cells. However, when the number of elicited presynaptic spikes is kept constant, the PR does not change. These results suggest that T cells change their responses in an activity-dependent manner through non-synaptic rather than synaptic plasticity. These changes might act as a gain-control mechanism. Depending on the previous activity, this gain could scale the relative impacts of synaptic inputs from other mechanoreceptors, versus the spike responses to tactile skin stimulation. This multi-tasking ability, and its flexible adaptation to previous activity, might make the T cell a key player in a preparatory network, enabling the leech to perform fast behavioral reactions to skin stimulation.

COMPARATIVE STUDY OF THE ANTINOCICEPTIVE EFFECT OF ETIFOXINE AND RETIGABINE IN RATS

Introduction: Etifoxine is a nonbenzodiazepine anxiolytic and anticonvulsant drug. It enhances GABAergic transmission directly by binding to β2 and/or β3 subunits of the GABAA receptor complex and indirectly via stimulation of neurosteroid production after the activation of 18 kDa translocator protein (TSPO). Retigabine is an anticonvulsant drug which activates low-threshold voltage-gated potassium channels. Anticonvulsant drugs reduce hyperexcitability and are currently extensively studied for possible antinociceptive activity. The aim of this study is to compare the antinociceptive effect of etifoxine and retigabine in rats. Materials and methods: The research included forty male Wistar rats, divided into five groups (n = 8). They were treated intraperitoneally with: 1st group (control) – saline 0,1ml/100g bw, 2nd group–metamizole natrii 150 mg/kg bw, 3rd group – etifoxine 50 mg/kg bw, 4th group –retigabine 5 mg/kg bw and 5th group – retigabine 15 mg/kg bw. The antinociceptive effect was evaluated with hot plate test and analgesy-meter test. The statistical analysis was performed using SPSS.17. Results: Etifoxine did not prolong the latency time in hot plate test and did not increase the withdrawal latency in analgesy-meter test, compared to the animals treated with saline. In hot plate test, retigabine in dose 15 mg/kg bw significantly increased the latency time at the second and third hour, compared to the control group (p<0.05). In analgesy-meter test, a significant increase of the withdrawal latency between retigabine and control animals occurred only at dose 15 mg/kg bw at first hour after single administration (p<0.05). Conclusions: The obtained experimental data show that etifoxine in dose 50 mg/kg bw does not have antinociceptive effect. Single administration of retigabine 15 mg/kg bw reduced painful thermal and mechanical stimuli in rats. The presence of KCNQ channels in the neuronal pathways of pain suggests that the antinociceptive effect of retigabine is maybe based on the activation of low-threshold potassium channels.

Erratum to: A Modeling Study of the Responses of the Lateral Superior Olive to Ipsilateral Sinusoidally Amplitude-Modulated Tones.

The lateral superior olive (LSO) is a brainstem nucleus that is classically understood to encode binaural information in high-frequency sounds. Previous studies have shown that LSO cells are sensitive to envelope interaural time difference in sinusoidally amplitude-modulated (SAM) tones (Joris and Yin, J Neurophysiol 73:1043–1062, 1995; Joris, J Neurophysiol 76:2137–2156, 1996) and that a subpopulation of LSO neurons exhibit low-threshold potassium currents mediated by Kv1 channels (Barnes-Davies et al., Eur J Neurosci 19:325–333, 2004). It has also been shown that in many LSO cells the average response rate to ipsilateral SAM tones decreases with modulation frequency above a few hundred Hertz (Joris and Yin, J Neurophysiol 79:253–269, 1998). This low-pass feature is not directly inherited from the inputs to the LSO since the response rate of these input neurons changes little with increasing modulation frequency. In the current study, an LSO cell model is developed to investigate mechanisms consistent with the responses described above, notably the emergent rate decrease with increasing frequency. The mechanisms explored included the effects of after-hyperpolarization (AHP) channels, the dynamics of low-threshold potassium channels (KLT), and the effects of background inhibition. In the model, AHP channels alone were not sufficient to induce the observed rate decrease at high modulation frequencies. The model also suggests that the background inhibition alone, possibly from the medial nucleus of the trapezoid body, can account for the small rate decrease seen in some LSO neurons, but could not explain the large rate decrease seen in other LSO neurons at high modulation frequencies. In contrast, both the small and large rate decreases were replicated when KLT channels were included in the LSO neuron model. These results support the conclusion that KLT channels may play a major role in the large rate decreases seen in some units and that background inhibition may be a contributing factor, a factor that could be adequate for small decreases.

The Effects of Spontaneous Random Activity on Information Transmission in an Auditory Brain Stem Neuron Model

This paper presents the effects of spontaneous random activity on information transmission in an auditory brain stem neuron model. In computer simulations, the supra-threshold synaptic current stimuli ascending from auditory nerve fibers (ANFs) were modeled by a filtered inhomogeneous Poisson process modulated by sinusoidal functions at a frequency of 220–3520 Hz with regard to the human speech spectrum. The stochastic sodium and stochastic high- and low-threshold potassium channels were incorporated into a single compartment model of the soma in spherical bushy neurons, so as to realize threshold fluctuations or a variation of spike firing times. The results show that the information rates estimated from the entropy of inter-spike intervals of spike trains tend toward a convex function of the spontaneous rates when the intensity of sinusoidal functions decreases. Furthermore, the results show that a convex function of the spontaneous rates tends to disappear as the frequency of the sinusoidal function increases, such that the phase-locked response can be unobserved. It is concluded that this sort of stochastic resonance (SR) phenomenon, which depends on the spontaneous rates with supra-threshold stimuli, can better enhance information transmission in a smaller intensity of sinusoidal functions within the human speech spectrum, like the situation in which the regular SR can enhance weak signals.

An investigation of dendritic delay in octopus cells of the mammalian cochlear nucleus

Octopus cells, located in the mammalian auditory brainstem, receive their excitatory synaptic input exclusively from auditory nerve fibers (ANFs). They respond with accurately timed spikes but are broadly tuned for sound frequency. Since the representation of information in the auditory nerve is well understood, it is possible to pose a number of questions about the relationship between the intrinsic electrophysiology, dendritic morphology, synaptic connectivity, and the ultimate functional role of octopus cells in the brainstem. This study employed a multi-compartmental Hodgkin-Huxley model to determine whether dendritic delay in octopus cells improves synaptic input coincidence detection in octopus cells by compensating for the cochlear traveling wave delay. The propagation time of post-synaptic potentials from synapse to soma was investigated. We found that the total dendritic delay was approximately 0.275 ms. It was observed that low-threshold potassium channels in the dendrites reduce the amplitude dependence of the dendritic delay of post-synaptic potentials. As our hypothesis predicted, the model was most sensitive to acoustic onset events, such as the glottal pulses in speech when the synaptic inputs were arranged such that the model's dendritic delay compensated for the cochlear traveling wave delay across the ANFs. The range of sound frequency input from ANFs was also investigated. The results suggested that input to octopus cells is dominated by high frequency ANFs.

A Modeling Study of the Responses of the Lateral Superior Olive to Ipsilateral Sinusoidally Amplitude-Modulated Tones

The lateral superior olive (LSO) is a brainstem nucleus that is classically understood to encode binaural information in high-frequency sounds. Previous studies have shown that LSO cells are sensitive to envelope interaural time difference in sinusoidally amplitude-modulated (SAM) tones (Joris and Yin, J Neurophysiol 73:1043–1062, 1995; Joris, J Neurophysiol 76:2137–2156, 1996) and that a subpopulation of LSO neurons exhibit low-threshold potassium currents mediated by Kv1 channels (Barnes-Davies et al., Eur J Neurosci 19:325–333, 2004). It has also been shown that in many LSO cells the average response rate to ipsilateral SAM tones decreases with modulation frequency above a few hundred Hertz (Joris and Yin, J Neurophysiol 79:253–269, 1998). This low-pass feature is not directly inherited from the inputs to the LSO since the response rate of these input neurons changes little with increasing modulation frequency. In the current study, an LSO cell model is developed to investigate mechanisms consistent with the responses described above, notably the emergent rate decrease with increasing frequency. The mechanisms explored included the effects of after-hyperpolarization (AHP) channels, the dynamics of low-threshold potassium channels (KLT), and the effects of background inhibition. In the model, AHP channels alone were not sufficient to induce the observed rate decrease at high modulation frequencies. The model also suggests that the background inhibition alone, possibly from the medial nucleus of the trapezoid body, can account for the small rate decrease seen in some LSO neurons, but could not explain the large rate decrease seen in other LSO neurons at high modulation frequencies. In contrast, both the small and large rate decreases were replicated when KLT channels were included in the LSO neuron model. These results support the conclusion that KLT channels may play a major role in the large rate decreases seen in some units and that background inhibition may be a contributing factor, a factor that could be adequate for small decreases.

Nav1.9, G‐proteins, and nociceptors

Na_v1.9, G‐proteins, and nociceptors

Development of gerbil medial superior olive: integration of temporally delayed excitation and inhibition at physiological temperature.

The sensitivity of medial superior olive (MSO) neurons to tens of microsecond differences in interaural temporal delay (ITD) derives in part from their membrane electrical characteristics, kinetics and timing of excitatory and inhibitory inputs, and dendrite structure. However, maturation of these physiological and structural characteristics are little studied, especially in relationship to the onset of auditory experience. We showed, using brain slices at physiological temperature, that MSO neurons exhibited sensitivity to simulated temporally delayed (TD) EPSCs (simEPSC), injected through the recording electrode, by the initial phase of hearing onset at P10, and TD sensitivity was reduced by block of low threshold potassium channels. The spike generation mechanism matured between P10 and P16 to support TD sensitivity to adult-like excitatory stimuli (1-4 ms duration) by P14. IPSP duration was shorter at physiological temperature than reported for lower temperatures, was longer than EPSP duration at young ages, but approached the duration of EPSPs by P16, when hearing thresholds neared maturity. Dendrite branching became less complex over a more restricted time frame between P10 and P12. Because many physiological and structural properties approximated mature values between P14 and P16, we studied temporal integration of simEPSCs and IPSPs at P15. Only a narrow range of relative onset times (< 1 ms) yielded responses showing sensitivity to TD. We propose that shaping of excitatory circuitry to mediate TD sensitivity can begin before airborne sound is detectable, and that inhibitory inputs having suboptimal neural delays may then be pruned by cellular mechanisms activated by sensitivity to ITD.

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.

Low-threshold potassium channels and a low-threshold calcium channel regulate Ca 2+ spike firing in the dendrites of cerebellar Purkinje neurons: a modeling study

Various types of voltage-gated ion channels are distributed along the dendrites of neurons in the central nervous system. We have recently shown experimentally that the dendrites of cerebellar Purkinje neurons contain low-threshold voltage-gated Ca 2+ channels and low-threshold voltage-gated K + channels. Although we found that these channels are involved in regulating the onset of Ca 2+-dependent action potentials in the dendrites, we were unable to identify which of the known types of low-threshold Ca 2+ channels and K + channels were responsible, since there was no reliable method of discriminating between them. Here, we have built a detailed compartmental model of a Purkinje neuron by incorporating two types of low-threshold Ca 2+ channel (T-type and class-E, or R-type) and two types of low-threshold K + channel (A-type and D-type), in addition to another eight voltage-gated channel types, using a compartmental model neuron simulator. The model reproduces the basic features of the depolarization-induced responses of Purkinje neurons, such as fast Na + spikes in the soma, Ca 2+ spikes in the dendrites, the slow onset of Ca 2+ spikes, repetitive Ca 2+ spikes in the presence of TTX, the marked shortening of Ca 2+ spike onset in the presence of 4-aminopydridine, and the longer Ca 2+ spike onset in the presence of Ni 2+. Our model shows that the D-type K + channel and the class-E Ca 2+ channel regulate the onset of depolarization-induced Ca 2+ spikes in Purkinje neurons. These channels might be involved in integrating synaptic inputs in Purkinje neurons.