A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons

The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182–187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41–51, 1986). Kalluri et al. ( J Neurophysiol 104: 2034–2051, 2010) proposed that regularity is controlled by the density of low-voltage-activated potassium currents ( IKL). To examine the impact of IKL on spike timing regularity, we implemented a single-compartment model with three conductances known to be present in the vestibular ganglion: transient sodium ( gNa), low-voltage-activated potassium ( gKL), and high-voltage-activated potassium ( gKH). Consistent with in vitro observations, removing gKL depolarized resting potential, increased input resistance and membrane time constant, and converted current step-evoked firing patterns from transient (1 spike at current onset) to sustained (many spikes). Modeled neurons were driven with a time-varying synaptic conductance that captured the random arrival times and amplitudes of glutamate-driven synaptic events. In the presence of gKL, spiking occurred only in response to large events with fast onsets. Models without gKL exhibited greater integration by responding to the superposition of rapidly arriving events. Three synaptic conductance were modeled, each with different kinetics to represent a variety of different synaptic processes. In response to all three types of synaptic conductance, models containing gKL produced spike trains with irregular interspike intervals. Only models lacking gKL when driven by rapidly arriving small excitatory postsynaptic currents were capable of generating regular spiking.

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Similarities in the Biophysical Properties of Spiral-Ganglion and Vestibular-Ganglion Neurons in Neonatal Rats

Frontiers in Neuroscience ◽

10.3389/fnins.2021.710275 ◽

2021 ◽

Vol 15 ◽

Author(s):

Radha Kalluri

Keyword(s):

Sensory Modality ◽

Spiral Ganglion ◽

Input Resistance ◽

Resting Potential ◽

Biophysical Properties ◽

Firing Patterns ◽

Vestibular Ganglion ◽

Large Current ◽

Ganglion Neurons ◽

Diverse Groups

The membranes of auditory and vestibular afferent neurons each contain diverse groups of ion channels that lead to heterogeneity in their intrinsic biophysical properties. Pioneering work in both auditory- and vestibular-ganglion physiology have individually examined this remarkable diversity, but there are few direct comparisons between the two ganglia. Here the firing patterns recorded by whole-cell patch-clamping in neonatal vestibular- and spiral ganglion neurons are compared. Indicative of an overall heterogeneity in ion channel composition, both ganglia exhibit qualitatively similar firing patterns ranging from sustained-spiking to transient-spiking in response to current injection. The range of resting potentials, voltage thresholds, current thresholds, input-resistances, and first-spike latencies are similarly broad in both ganglion groups. The covariance between several biophysical properties (e.g., resting potential to voltage threshold and their dependence on postnatal age) was similar between the two ganglia. Cell sizes were on average larger and more variable in VGN than in SGN. One sub-group of VGN stood out as having extra-large somata with transient-firing patterns, very low-input resistance, fast first-spike latencies, and required large current amplitudes to induce spiking. Despite these differences, the input resistance per unit area of the large-bodied transient neurons was like that of smaller-bodied transient-firing neurons in both VGN and SGN, thus appearing to be size-scaled versions of other transient-firing neurons. Our analysis reveals that although auditory and vestibular afferents serve very different functions in distinct sensory modalities, their biophysical properties are more closely related by firing pattern and cell size than by sensory modality.

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Ion Channels Set Spike Timing Regularity of Mammalian Vestibular Afferent Neurons

Journal of Neurophysiology ◽

10.1152/jn.00396.2010 ◽

2010 ◽

Vol 104 (4) ◽

pp. 2034-2051 ◽

Cited By ~ 54

Author(s):

Radha Kalluri ◽

Jingbing Xue ◽

Ruth Anne Eatock

Keyword(s):

Ion Channels ◽

Firing Pattern ◽

Low Voltage ◽

Spike Timing ◽

Resting Potential ◽

Firing Patterns ◽

Different Temperatures ◽

The Difference ◽

Current Steps ◽

Whole Cell Recordings

In the mammalian vestibular nerve, some afferents have highly irregular interspike intervals and others have highly regular intervals. To investigate whether spike timing is determined by the afferents' ion channels, we studied spiking activity in their cell bodies, isolated from the vestibular ganglia of young rats. Whole cell recordings were made with the perforated-patch method. As previously reported, depolarizing current steps revealed distinct firing patterns. Transient neurons fired one or two onset spikes, independent of current level. Sustained neurons were more heterogeneous, firing either trains of spikes or a spike followed by large voltage oscillations. We show that the firing pattern categories are robust, occurring at different temperatures and ages, both in mice and in rats. A difference in average resting potential did not cause the difference in firing patterns, but contributed to differences in afterhyperpolarizations. A low-voltage-activated potassium current ( ILV) was previously implicated in the transient firing pattern. We show that ILV grew from the first to second postnatal week and by the second week comprised Kv1 and Kv7 (KCNQ) components. Blocking ILV converted step-evoked firing patterns from transient to sustained. Separated from their normal synaptic inputs, the neurons did not spike spontaneously. To test whether the firing-pattern categories might correspond to afferent populations of different regularity, we injected simulated excitatory postsynaptic currents at pseudorandom intervals. Sustained neurons responded to a given pattern of input with more regular firing than did transient neurons. Pharmacological block of ILV made firing more regular. Thus ion channel differences that produce transient and sustained firing patterns in response to depolarizing current steps can also produce irregular and regular spike timing.

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Muscarinic acetylcholine receptors modulate HCN channel properties in vestibular ganglion neurons

10.1101/2021.12.30.474193 ◽

2022 ◽

Author(s):

Daniel Bronson ◽

Radha Kalluri

Keyword(s):

Signaling Cascades ◽

Hcn Channels ◽

Type I ◽

Hcn Channel ◽

Firing Patterns ◽

Vestibular Ganglion ◽

Muscarinic Acetylcholine ◽

Efferent Neurons ◽

Ganglion Neurons ◽

Channel Properties

Vestibular efferent neurons play an important role in shaping vestibular afferent excitability and accordingly, on the information encoded by their spike patterns. Efferent-modulation is linked to muscarinic signaling cascades that affect ion channel conductances, most notably low-voltage gated potassium channels such as KCNQ. Here we tested and found that muscarinic signaling cascades also modulate hyperpolarization-activated cyclic-nucleotide gated channels (HCN). HCN channels play a key role in controlling spike-timing regularity and a non-chemical form of transmission between type I hair cells and vestibular afferents. The impact of cholinergic efferent input on HCN channels was assessed using voltage-clamp methods, which measure currents in the disassociated cell bodies of vestibular ganglion neurons (VGN). Membrane properties in VGN were characterized before and after administration of the muscarinic acetylcholine receptor (mAChR) agonist Oxotremorine-M (Oxo-M). We found that Oxo-M shifted the voltage-activation range of HCN channels in the positive direction by 4.1 +/- 1.1 mV, which more than doubled the available current when held near rest at -60 mV (a 184 +/- 90.1% increase, n=19). This effect was not blocked by pre-treating the cells with a KCNQ channel blocker, linopirdine, which suggests that this effect is not dependent on KCNQ currents. We also found that HCN channel properties in the baseline condition and sensitivity to mAChR activation depended on cell size and firing patterns. Large-bodied neurons with onset firing patterns had the most depolarized activation range and least sensitivity to mAChR activation. Together, our results highlight the complex and dynamic regulation of HCN channels in VGN.

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Molecular identity, ontogeny, and cAMP modulation of the hyperpolarization-activated current in vestibular ganglion neurons

Journal of Neurophysiology ◽

10.1152/jn.00337.2012 ◽

2012 ◽

Vol 108 (8) ◽

pp. 2264-2275 ◽

Cited By ~ 12

Author(s):

Angélica Almanza ◽

Enoch Luis ◽

Francisco Mercado ◽

Rosario Vega ◽

Enrique Soto

Keyword(s):

Current Density ◽

Small Cells ◽

Resting Potential ◽

Afferent Neuron ◽

Intracellular Camp ◽

Rt Pcr ◽

Patch Clamp Technique ◽

Vestibular Ganglion ◽

Hyperpolarization Activated Current ◽

Ganglion Neurons

Properties, developmental regulation, and cAMP modulation of the hyperpolarization-activated current ( Ih) were investigated by the whole cell patch-clamp technique in vestibular ganglion neurons of the rat at two postnatal stages (P7–10 and P25–28). In addition, by RT-PCR and immunohistochemistry the identity and distribution of hyperpolarization-activated and cyclic nucleotide-gated channel (HCN) isoforms that generate Ih were investigated. Ih current density was larger in P25–28 than P7–10 rats, increasing 410% for small cells (<30 pF) and 200% for larger cells (>30 pF). The half-maximum activation voltage ( V1/2) of Ih was −102 mV in P7–10 rats and in P25–28 rats shifted 7 mV toward positive voltages. At both ages, intracellular cAMP increased Ih current density, decreased its activation time constant (τ), and resulted in a rightward shift of V1/2 by 9 mV. Perfusion of 8-BrcAMP increased Ih amplitude and speed up its activation kinetics. Ih was blocked by Cs+, zatebradine, and ZD7288. As expected, these drugs also reduced the voltage sag caused with hyperpolarizing pulses and prevented the postpulse action potential generation without changes in the resting potential. RT-PCR analysis showed that HCN1 and HCN2 subunits were predominantly amplified in vestibular ganglia and end organs and HCN3 and HCN4 to a lesser extent. Immunohistochemistry showed that the four HCN subunits were differentially expressed (HCN1 > HCN2 > HCN3 ≥ HCN4) in ganglion slices and in cultured neurons at both P7–10 and P25–28 stages. Developmental changes shifted V1/2 of Ih closer to the resting membrane potential, increasing its functional role. Modulation of Ih by cAMP-mediated signaling pathway constitutes a potentially relevant control mechanism for the modulation of afferent neuron discharge.

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Potassium currents and their modulation by muscarine and substance P in neuronal cultures from adult guinea pig celiac ganglia

Journal of Neurophysiology ◽

10.1152/jn.1993.69.5.1632 ◽

1993 ◽

Vol 69 (5) ◽

pp. 1632-1644 ◽

Cited By ~ 32

Author(s):

S. Vanner ◽

R. J. Evans ◽

S. G. Matsumoto ◽

A. Surprenant

Keyword(s):

Substance P ◽

Guinea Pig ◽

Action Potential ◽

Potassium Current ◽

Potassium Currents ◽

Resting Potential ◽

Time Constants ◽

Whole Cell ◽

Calcium Dependent ◽

Ganglion Neurons

1. Intracellular microelectrode and whole-cell patch-clamp recordings were obtained from adult guinea pig celiac ganglion neurons grown in tissue culture for 7-14 days. Over 90% of neurons showed phasic-type action-potential discharge with the use of either type of recording electrode; they stained immunohistochemically for catecholamines, tyrosine hydroxylase, and neuropeptide Y. Input resistance (140 M omega) and action-potential amplitude (103 mV) were significantly greater with whole-cell than with microelectrode recordings, but other passive electrical properties were similar. 2. Five potassium currents were characterized: an apamin-sensitive after hyperpolarizing current (IAHP), an apamin and tetraethylammonium-insensitive slow IAHP, an M-like current, a transient outward IA current, and a delayed rectifier IK current. A hyperpolarization-activated cationic Ih current was also present. The first three currents were not observed with whole-cell recordings. 3. Cadmium (200 microM), cobalt (1 mM), lanthanum (30 microM), or a low calcium/high magnesium solution blocked both IAHPS and the M-like current; barium (1 mM) also blocked these currents. 4. Kinetics of the M-like current were best described by a double exponential fit to deactivating tail currents with time constants of 50 and 390 ms at -50 mV. The apamin-sensitive and slow IAHP decayed exponentially with time constants of 145 ms and 3.5 s, respectively. There was no correlation between occurrence of M-like current (95% of neurons) and slow IAHP (40% of neurons), nor any correlation between magnitude of M-like current and IAHP in those cells exhibiting both currents. 5. Muscarine and substance P (SP) caused depolarizations or inward currents (under voltage clamp) at the resting potential (-55 mV) associated with a decreased membrane conductance. The slow IAHP and the M-like current, but not the apamin-sensitive IAHP nor the IA, were blocked by muscarine and SP (IC50 3 microM and 100 nM, respectively). Muscarine and SP also decreased a "leak" potassium current. 6. We conclude that celiac neurons express two calcium-dependent IAHP currents and a calcium-dependent M-current; these are seen by fine-tipped intracellular microelectrodes but not by whole-cell patch electrodes. These currents are not required for spike frequency accommodation. Muscarine and SP reduce these currents, as well as voltage-independent leakage potassium current.

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Optimized Strategic Planning of Future Norwegian Low-Voltage Networks with a Genetic Algorithm Applying Empirical Electric Vehicle Charging Data

Electricity ◽

10.3390/electricity2010006 ◽

2021 ◽

Vol 2 (1) ◽

pp. 91-109

Author(s):

Julian Wruk ◽

Kevin Cibis ◽

Matthias Resch ◽

Hanne Sæle ◽

Markus Zdrallek

Keyword(s):

Genetic Algorithm ◽

Electric Vehicle ◽

Electric Vehicles ◽

Low Voltage ◽

Network Planning ◽

Voltage Regulation ◽

Electric Vehicle Charging ◽

Vehicle Charging ◽

The Impact

This article outlines methods to facilitate the assessment of the impact of electric vehicle charging on distribution networks at planning stage and applies them to a case study. As network planning is becoming a more complex task, an approach to automated network planning that yields the optimal reinforcement strategy is outlined. Different reinforcement measures are weighted against each other in terms of technical feasibility and costs by applying a genetic algorithm. Traditional reinforcements as well as novel solutions including voltage regulation are considered. To account for electric vehicle charging, a method to determine the uptake in equivalent load is presented. For this, measured data of households and statistical data of electric vehicles are combined in a stochastic analysis to determine the simultaneity factors of household load including electric vehicle charging. The developed methods are applied to an exemplary case study with Norwegian low-voltage networks. Different penetration rates of electric vehicles on a development path until 2040 are considered.

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Uncontrolled Electric Vehicle Charging Impacts on Distribution Electric Power Systems with Primarily Residential, Commercial or Industrial Loads

Energies ◽

10.3390/en14061688 ◽

2021 ◽

Vol 14 (6) ◽

pp. 1688 ◽

Cited By ~ 1

Author(s):

C. Birk Jones ◽

Matthew Lave ◽

William Vining ◽

Brooke Marshall Garcia

Keyword(s):

Power Systems ◽

Electric Power ◽

Low Voltage ◽

Peak Load ◽

Electric Power Systems ◽

Primary System ◽

Maximum Increase ◽

Actual Distribution ◽

The Impact ◽

Ev Charging

An increase in Electric Vehicles (EV) will result in higher demands on the distribution electric power systems (EPS) which may result in thermal line overloading and low voltage violations. To understand the impact, this work simulates two EV charging scenarios (home- and work-dominant) under potential 2030 EV adoption levels on 10 actual distribution feeders that support residential, commercial, and industrial loads. The simulations include actual driving patterns of existing (non-EV) vehicles taken from global positioning system (GPS) data. The GPS driving behaviors, which explain the spatial and temporal EV charging demands, provide information on each vehicles travel distance, dwell locations, and dwell durations. Then, the EPS simulations incorporate the EV charging demands to calculate the power flow across the feeder. Simulation results show that voltage impacts are modest (less than 0.01 p.u.), likely due to robust feeder designs and the models only represent the high-voltage (“primary”) system components. Line loading impacts are more noticeable, with a maximum increase of about 15%. Additionally, the feeder peak load times experience a slight shift for residential and mixed feeders (≈1 h), not at all for the industrial, and 8 h for the commercial feeder.

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Petasin and isopetasin reduce CGRP release from trigeminal afferents indicating an inhibitory effect on TRPA1 and TRPV1 receptor channels

The Journal of Headache and Pain ◽

10.1186/s10194-021-01235-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Johanna Kleeberg-Hartmann ◽

Birgit Vogler ◽

Karl Messlinger

Keyword(s):

Inhibitory Effect ◽

Transient Receptor Potential Channels ◽

Mustard Oil ◽

Root Extract ◽

Dependent Manner ◽

Trpv1 Receptor ◽

Cgrp Release ◽

Ganglion Neurons ◽

Sites Of Action ◽

The Impact

Abstract Background Butterbur root extract with its active ingredients petasin and isopetasin has been used in the prophylactic treatment of migraine for years, while its sites of action are not completely clear. Calcitonin gene-related peptide (CGRP) is known as a biomarker and promoting factor of migraine. We set out to investigate the impact of petasins on the CGRP release from trigeminal afferents induced by activation of the calcium conducting transient receptor potential channels (TRPs) of the subtypes TRPA1 and TRPV1. Methods We used well-established in vitro preparations, the hemisected rodent skull and dissected trigeminal ganglia, to examine the CGRP release from rat and mouse cranial dura mater and trigeminal ganglion neurons, respectively, after pre-incubation with petasin and isopetasin. Mustard oil and capsaicin were used to stimulate TRPA1 and TRPV1 receptor channels. CGRP concentrations were measured with a CGRP enzyme immunoassay. Results Pre-incubation with either petasin or isopetasin reduced mustard oil- and capsaicin-evoked CGRP release compared to vehicle in an approximately dose-dependent manner. These results were validated by additional experiments with mice expressing functionally deleted TRPA1 or TRPV1 receptor channels. Conclusions Earlier findings of TRPA1 receptor channels being involved in the site of action of petasin and isopetasin are confirmed. Furthermore, we suggest an important inhibitory effect on TRPV1 receptor channels and assume a cooperative action between the two TRP receptors. These mechanisms may contribute to the migraine prophylactic effect of petasins.

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