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

ABSTRACT: 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.

SUBMITTER: Boeri J

PROVIDER: S-EPMC8139835 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Boeri Juliette J Meunier Claude C Le Corronc Hervé H Branchereau Pascal P Timofeeva Yulia Y Lejeune François-Xavier FX Mouffle Christine C Arulkandarajah Hervé H Mangin Jean Marie JM Legendre Pascal P Czarnecki Antonny A

eLife 20210426

Renshaw cells (V1<sup>R</sup>) 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 V1<sup>R</sup> during early embryonic development of the mouse spinal cord locomotor networks (E11.5-E16.5). We found that these interne ...[more]

PMID: 33899737

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Project description:We determine membrane capacitance, C as a function of dc voltage for the human embryonic kidney (HEK) cell. C was calculated from the admittance, Y, obtained during a voltage ramp when the HEK cell was held in whole-cell patch-clamp configuration. Y was determined at frequencies of 390.625 and from the measured current, i obtained with a dual-sinusoidal stimulus. We find that the fractional increase in the capacitance, C is small ( < 1%) and grows with the square of the voltage, Psi. C can be described by: C=C(0)(1+alpha(Psi+psi(s))2)[where C(0): Capacitance at 0 volts, psi(s): Difference in surface potential between cytoplasmic and extracellular leaflets and alpha: Proportionality constant]. We find that alpha and psi(s) are 0.120 (+/- 0.01) V(-2) and -0.073 (+/-0.017 V in solutions that contain ion channel blockers and 0.108 (+/- 0.29) V(-2) and -0.023 (+/- 0.009) V when 10 mM sodium salicylate was added to the extracellular solution. This suggests that salicylate does not affect the rate at which C grows with Psi, but reduces the charge asymmetry of the membrane. We also observe an additional linear differential capacitance of about (-46 fFV(-1)) in about 60% of the cells, this additional component acts simultaneously with the quadratic component and was not observed when salicylate was added to the solution. We suggest that the voltage dependent capacitance originates from electromechanical coupling either by electrostriction and/or Maxwell stress effects and estimate that a small electromechanical force (approximately equal to 1 pN) acts at physiological potentials. These results are relevant to understand the electromechanical coupling in outer hair cells (OHCs) of the mammalian cochlea, where an asymmetric bell-shaped C versus Psi relationship is observed upon application of a similar field. Prestin, a membrane protein expressed in OHCs is required to observe this function. When we compare the total charge contributions from HEK cell membrane (7 x 10(4) electrons, 10 pF cell) with that determined for prestin transfected cells (up to 5 x 10(6) electrons) we conclude that the charge contributions from the collective motion of membrane proteins and lipids in the field is dwarfed relative to that when prestin is present. We suggest that the capacitance-voltage relationships should be similar to that observed for HEK cells for OHCs that do not express prestin in their membranes.

Project description:The non-linear voltage-dependent hysteresis (Hys(V)) of voltage-gated ionic currents can be robustly activated by the isosceles-triangular ramp voltage (Vramp) through digital-to-analog conversion. Perturbations on this Hys(V) behavior play a role in regulating membrane excitability in different excitable cells. A variety of small molecules may influence the strength of Hys(V) in different types of ionic currents elicited by long-lasting triangular Vramp. Pirfenidone, an anti-fibrotic drug, decreased the magnitude of Ih's Hys(V) activated by triangular Vramp, while dexmedetomidine, an agonist of α2-adrenoceptors, effectively suppressed Ih as well as diminished the Hys(V) strength of Ih. Oxaliplatin, a platinum-based anti-neoplastic drug, was noted to enhance the Ih's Hys(V) strength, which is thought to be linked to the occurrence of neuropathic pain, while honokiol, a hydroxylated biphenyl compound, decreased Ih's Hys(V). Cell exposure to lutein, a xanthophyll carotenoid, resulted in a reduction of Ih's Hys(V) magnitude. Moreover, with cell exposure to UCL-2077, SM-102, isoplumbagin, or plumbagin, the Hys(V) strength of erg-mediated K+ current activated by triangular Vramp was effectively diminished, whereas the presence of either remdesivir or QO-58 respectively decreased or increased Hys(V) magnitude of M-type K+ current. Zingerone, a methoxyphenol, was found to attenuate Hys(V) (with low- and high-threshold loops) of L-type Ca2+ current induced by long-lasting triangular Vramp. The Hys(V) properties of persistent Na+ current (INa(P)) evoked by triangular Vramp were characterized by a figure-of-eight (i.e., ∞) configuration with two distinct loops (i.e., low- and high-threshold loops). The presence of either tefluthrin, a pyrethroid insecticide, or t-butyl hydroperoxide, an oxidant, enhanced the Hys(V) strength of INa(P). However, further addition of dapagliflozin can reverse their augmenting effects in the Hys(V) magnitude of the current. Furthermore, the addition of esaxerenone, mirogabalin, or dapagliflozin was effective in inhibiting the strength of INa(P). Taken together, the observed perturbations by these small-molecule modulators on Hys(V) strength in different types of ionic currents evoked during triangular Vramp are expected to influence the functional activities (e.g., electrical behaviors) of different excitable cells in vitro or in vivo.

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

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

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