Kv1 channels regulate variations in spike patterning and temporal reliability in the avian cochlear nucleus angularis

Diverse physiological phenotypes in a neuronal population can broaden the range of computational capabilities within a brain region. The avian cochlear nucleus angularis (NA) contains a heterogeneous population of neurons whose variation in intrinsic properties results in electrophysiological phenotypes with a range of sensitivities to temporally modulated input. The low-threshold potassium conductance (GKLT) is a key feature of neurons involved in fine temporal structure coding for sound localization but a role for these channels in intensity or spectrotemporal coding has not been established. To determine whether GKLT affects the phenotypical variation and temporal properties of NA neurons, we applied dendrotoxin (DTX), a potent antagonist of Kv1-type potassium channels, to chick brain stem slices in vitro during whole-cell patch clamp recordings. We found a cell-type specific subset of NA neurons were sensitive to DTX: single-spiking NA neurons were most profoundly affected, as well as a subset of tonic firing neurons. Both tonic I (phasic onset bursting) and tonic II (delayed firing) neurons showed DTX sensitivity in their firing rate and phenotypical firing pattern. Tonic III neurons were unaffected. Spike time reliability and fluctuation sensitivity measured in DTX-sensitive NA neurons was also reduced with DTX. Finally, DTX reduced spike threshold adaptation in these neurons, suggesting that GKLT contributes to the temporal properties that allow coding of rapid changes in the inputs to NA neurons. These results suggest that variation in Kv1 channel expression may be a key factor in functional diversity in the avian cochlear nucleus.

Kv1 channels regulate variations in spike patterning and temporal reliability in the avian cochlear nucleus angularis

Diverse physiological phenotypes in a neuronal population can broaden the range of computational capabilities within a brain region. The avian cochlear nucleus angularis (NA) contains a heterogeneous population of neurons whose variation in intrinsic properties results in electrophysiological phenotypes with a range of sensitivities to temporally modulated input. The low-threshold potassium conductance (GKLT) is a key feature of neurons involved in fine temporal structure coding for sound localization but a role for these channels in intensity or spectrotemporal coding has not been established. To determine whether GKLT affects the phenotypical variation and temporal properties of NA neurons, we applied dendrotoxin (DTX), a potent antagonist of Kv1-type potassium channels, to chick brain stem slices in vitro during whole-cell patch clamp recordings. We found a cell-type specific subset of NA neurons were sensitive to DTX: single-spiking NA neurons were most profoundly affected, as well as a subset of tonic firing neurons. Both tonic I (phasic onset bursting) and tonic II (delayed firing) neurons showed DTX sensitivity in their firing rate and phenotypical firing pattern. Tonic III neurons were unaffected. Spike time reliability and fluctuation sensitivity measured in DTX-sensitive NA neurons was also reduced with DTX. Finally, DTX reduced spike threshold adaptation in these neurons, suggesting that GKLT contributes to the temporal properties that allow coding of rapid changes in the inputs to NA neurons. These results suggest that variation in Kv1 channel expression may be a key factor in functional diversity in the avian cochlear nucleus.

On the electrical passivity of astrocyte potassium conductance

Predominant expression of leak-type K+ channels provides astrocytes a high membrane permeability to K+ ions and a hyperpolarized membrane potential that are crucial for astrocyte function in brain homeostasis. In functionally mature astrocytes, the expression of leak K+ channels creates a unique membrane K+ conductance that lacks voltage-dependent rectification. Accordingly, the conductance is named ohmic or passive K+ conductance. Several inwardly rectifiers and two-pore domain K+ channels have been investigated for their contributions to passive conductance. Meanwhile, gap junctional coupling has been postulated to underlie the passive behavior of membrane conductance. It is now clear that the intrinsic properties of K+ channels and gap junctional coupling can each act alone or together to bring about a passive behavior of astrocyte conductance. Additionally, while the passive conductance can generally be viewed as a K+ conductance, the actual representation of this conductance is a combined expression of multiple known and unknown K+ channels, which has been further modified by the intricate morphology of individual astrocytes and syncytial gap junctional coupling. The expression of the inwardly rectifying K+ channels explains the inward-going component of passive conductance disobeying Goldman-Hodgkin-Kate (GHK) constant field outward rectification. However, the K+ channels encoding the outward-going passive currents remain to be determined in the future. Here, we review our current understanding of ion channels and biophysical mechanisms engaged in the passive astrocyte K+ conductance, propose new studies to resolve this long-standing puzzle in astrocyte physiology, and discuss the functional implication(s) of passive behavior of K+ conductance on astrocyte physiology.

The exponential tracking and disturbance rejection of the propagated membrane action potential with conductance coefficient feedforward controllers

In the early 1950's, using their experimental data, Hodgkin and Huxley constructed the sodium and potassium conductance feedback controllers for their mathematical model of the flow of electric current through the surface membrane of a giant nerve fibre. In this paper, we re-formulate the construction as a problem of exponential tracking and disturbance rejection and then re-construct new conductance feedforward controllers in the more complicated case of a propagated action potential. The dynamics of the potential is governed by the Hodgkin-Huxley's partial differential equation (PDE) model. The problem is solved for any current disturbances and potential references and conductance coefficient feedforward controllers are designed by using the method of variable transform. It is proved that, under the designed feedforward controllers, the potential tracks exponentially a desired potential reference uniformly on an interval of one unit and the reference satisfies the controlled PDE model except an initial condition. A numerical example shows that the simulated action potential and sodium and potassium conductances are close to the experimental observations.

Robustness of neuronal tuning to binaural sound localization cues against age-related loss of inhibitory synaptic inputs

Sound localization relies on minute differences in the timing and intensity of sound arriving at both ears. Neurons of the lateral superior olive (LSO) in the brainstem process these interaural disparities by precisely detecting excitatory and inhibitory synaptic inputs. Aging generally induces selective loss of inhibitory synaptic transmission along the entire auditory pathways, including the reduction of inhibitory afferents to LSO. Electrophysiological recordings in animals, however, reported only minor functional changes in aged LSO. The perplexing discrepancy between anatomical and physiological observations suggests a role for activity-dependent plasticity that would help neurons retain their binaural tuning function despite loss of inhibitory inputs. To explore this hypothesis, we use a computational model of LSO to investigate mechanisms underlying the observed functional robustness against age-related loss of inhibitory inputs. The LSO model is an integrate-and-fire type enhanced with a small amount of low-voltage activated potassium conductance and driven with (in)homogeneous Poissonian inputs. Without synaptic input loss, model spike rates varied smoothly with interaural time and level differences, replicating empirical tuning properties of LSO. By reducing the number of inhibitory afferents to mimic age-related loss of inhibition, overall spike rates increased, which negatively impacted binaural tuning performance, measured as modulation depth and neuronal discriminability. To simulate a recovery process compensating for the loss of inhibitory fibers, the strength of remaining inhibitory inputs was increased. By this modification, effects of inhibition loss on binaural tuning were considerably weakened, leading to an improvement of functional performance. These neuron-level observations were further confirmed by population modeling, in which binaural tuning properties of multiple LSO neurons were varied according to empirical measurements. These results demonstrate the plausibility that homeostatic plasticity could effectively counteract known age-dependent loss of inhibitory fibers in LSO and suggest that behavioral degradation of sound localization might originate from changes occurring more centrally.

The exponential tracking and disturbance rejection of the propagated membrane action potential with conductance coefficient feedforward controllers

In the early 1950's, using their experimental data, Hodgkin and Huxley constructed the sodium and potassium conductance feedback controllers for their mathematical model of the flow of electric current through the surface membrane of a giant nerve fibre. In this paper, we re-formulate the construction as a problem of exponential tracking and disturbance rejection and then re-construct new conductance feedforward controllers in the more complicated case of a propagated action potential. The dynamics of the potential is governed by the Hodgkin-Huxley's partial differential equation (PDE) model. The problem is solved for any current disturbances and potential references and conductance coefficient feedforward controllers are designed by using the method of variable transform. It is proved that, under the designed feedforward controllers, the potential tracks exponentially a desired potential reference uniformly on an interval of one unit and the reference satisfies the controlled PDE model except an initial condition. A numerical example shows that the simulated action potential and sodium and potassium conductances are close to the experimental observations.

Investigating the Cocaine-induced Reduction of Potassium Current on the Generation of Action Potentials Using a Computational Model

Introduction: Drugs of abuse, including cocaine, affect different brain regions and lead to pathological memories. These abnormal memories may occur due to the changes in synaptic transmissions or variations in synaptic properties of neurons. It has been shown that cocaine inhibits delayed rectifying potassium currents in affected regions of the brain and can have a role in the formation of pathological memories. Purpose: This study investigates how the change in the conductance of delayed rectifying potassium channels can affect the produced action potentials using a computational model. Methods: We present a computational model with different channels and receptors, including sodium, potassium, calcium, NMDARs, and AMPARs, which can produce burst-type action potentials. In the simulations, by changing the delayed rectifying potassium conductance bifurcation diagram is calculated. Conclusion: Results show that for a specific range of potassium conductance, a chaotic regime emerges in produced action potentials. These chaotic oscillations may play a role in inducing abnormal memories.

Neuropeptide S Receptor Stimulation Excites Principal Neurons in Murine Basolateral Amygdala through a Calcium-Dependent Decrease in Membrane Potassium Conductance

Background: The neuropeptide S system, consisting of the 20 amino acid neuropeptide NPS and its G-protein-coupled receptor (GPCR) neuropeptide S receptor 1 (NPSR1), has been studied intensively in rodents. Although there is a lot of data retrieved from behavioral studies using pharmacology or genetic interventions, little is known about intracellular signaling cascades in neurons endogenously expressing the NPSR1. Methods: To elucidate possible G-protein-dependent signaling and effector systems, we performed whole-cell patch-clamp recordings on principal neurons of the anterior basolateral amygdala of mice. We used pharmacological interventions to characterize the NPSR1-mediated current induced by NPS application. Results: Application of NPS reliably evokes inward-directed currents in amygdalar neurons recorded in brain slice preparations of male and female mice. The NPSR1-mediated current had a reversal potential near the potassium reversal potential (EK) and was accompanied by an increase in membrane input resistance. GDP-β-S and BAPTA, but neither adenylyl cyclase inhibition nor 8-Br-cAMP, abolished the current. Intracellular tetraethylammonium or 4-aminopyridine reduced the NPS-evoked current. Conclusion: NPSR1 activation in amygdalar neurons inhibits voltage-gated potassium (K+) channels, most likely members of the delayed rectifier family. Intracellularly, Gαq signaling and calcium ions seem to be mandatory for the observed current and increased neuronal excitability.

The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain

Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine—another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice.

Two opposite voltage-dependent currents control the unusual early development pattern of embryonic Renshaw cell electrical activity

Renshaw cells (V1R) are excitable as soon as they reach their final location next to the spinal motoneurons and are functionally heterogeneous. Using multiple experimental approaches, in combination with biophysical modeling and dynamical systems theory, we analyzed, for the first time, the mechanisms underlying the electrophysiological properties of V1R during early embryonic development of the mouse spinal cord locomotor networks (E11.5-E16.5). We found that these interneurons are subdivided into several functional clusters from E11.5 and then display an unexpected transitory involution process during which they lose their ability to sustain tonic firing. We demonstrated that the essential factor controlling the diversity of the discharge pattern of embryonic V1R is the ratio of a persistent sodium conductance to a delayed rectifier potassium conductance. Taken together, our results reveal how a simple mechanism, based on the synergy of two voltage-dependent conductances that are ubiquitous in neurons, can produce functional diversity in embryonic V1R and control their early developmental trajectory.