Acute effects of the imidacloprid metabolite desnitro-imidacloprid on human nACh receptors relevant for neuronal signaling

Several neonicotinoids have recently been shown to activate the nicotinic acetylcholine receptor (nAChR) on human neurons. Moreover, imidacloprid (IMI) and other members of this pesticide family form a set of diverse metabolites within crops. Among these, desnitro-imidacloprid (DN-IMI) is of special toxicological interest, as there is evidence (i) for human dietary exposure to this metabolite, (ii) and that DN-IMI is a strong trigger of mammalian nicotinic responses. We set out here to quantify responses of human nAChRs to DN-IMI and an alternative metabolite, IMI-olefin. To evaluate toxicological hazards, these data were then compared to those of IMI and nicotine. Ca2+-imaging experiments on human neurons showed that DN-IMI exhibits an agonistic effect on nAChRs at sub-micromolar concentrations (equipotent with nicotine) while IMI-olefin activated the receptors less potently (in a similar range as IMI). Direct experimental data on the interaction with defined receptor subtypes were obtained by heterologous expression of various human nAChR subtypes in Xenopus laevis oocytes and measurement of the transmembrane currents evoked by exposure to putative ligands. DN-IMI acted on the physiologically important human nAChR subtypes α7, α3β4, and α4β2 (high-sensitivity variant) with similar potency as nicotine. IMI and IMI-olefin were confirmed as nAChR agonists, although with 2–3 orders of magnitude lower potency. Molecular docking studies, using receptor models for the α7 and α4β2 nAChR subtypes supported an activity of DN-IMI similar to that of nicotine. In summary, these data suggest that DN-IMI functionally affects human neurons similar to the well-established neurotoxicant nicotine by triggering α7 and several non-α7 nAChRs.

The timescale and magnitude of aperiodic activity decreases with cortical depth in humans, macaques and mice

Cortical dynamics obey a 1/f power law, exhibiting an exponential decay of spectral power with increasing frequency. The slope and offset of this 1/f decay reflect the timescale and magnitude of aperiodic neural activity, respectively. These properties are tightly linked to cellular and circuit mechanisms (e.g. excitation:inhibition balance, firing rates) as well as cognitive processes (perception, memory, state). However, the physiology underlying the 1/f power law in cortical dynamics is not well understood. Here, we compared laminar recordings from human, macaque and mouse cortex to evaluate how 1/f aperiodic dynamics vary across cortical layers and species. We report that 1/f slope is steepest in superficial layers and flattest in deep layers in each species. Additionally, the magnitude of this 1/f decay is greatest in superficial cortex and decreases with depth. Both of these findings can be accounted for by a simple model in which transmembrane currents have longer time constants and greater densities in superficial cortical layers. Together, our results provide novel mechanistic insight into aperiodic dynamics in cortex and suggest that the timescale and magnitude of aperiodic cortical currents decrease with cortical depth.

A thermodynamic description for physiological transmembrane transport

A general formulation for both passive and active transmembrane transport is derived from basic thermodynamical principles. The derivation takes into account the energy required for the motion of molecules across membranes and includes the possibility of modeling asymmetric flow. Transmembrane currents can then be described by the general model in the case of electrogenic flow. As it is desirable in new models, it is possible to derive other well-known expressions for transmembrane currents as particular cases of the general formulation. For instance, the conductance-based formulation for current turns out to be a linear approximation of the general formula for current. Also, under suitable assumptions, other formulas for current based on electrodiffusion, like the constant field approximation by Goldman, can be recovered from the general formulation. The applicability of the general formulations is illustrated first with fits to existing data, and after, with models of transmembrane potential dynamics for pacemaking cardiocytes and neurons. The general formulations presented here provide a common ground for the biophysical study of physiological phenomena that depend on transmembrane transport.

TRPM7-Mediated Calcium Transport in HAT-7 Ameloblasts

TRPM7 plays an important role in cellular Ca2+, Zn2+ and Mg2+ homeostasis. TRPM7 channels are abundantly expressed in ameloblasts and, in the absence of TRPM7, dental enamel is hypomineralized. The potential role of TRPM7 channels in Ca2+ transport during amelogenesis was investigated in the HAT-7 rat ameloblast cell line. The cells showed strong TRPM7 mRNA and protein expression. Characteristic TRPM7 transmembrane currents were observed, which increased in the absence of intracellular Mg2+ ([Mg2+]i), were reduced by elevated [Mg2+]i, and were inhibited by the TRPM7 inhibitors NS8593 and FTY720. Mibefradil evoked similar currents, which were suppressed by elevated [Mg2+]i, reducing extracellular pH stimulated transmembrane currents, which were inhibited by FTY720. Naltriben and mibefradil both evoked Ca2+ influx, which was further enhanced by the acidic intracellular conditions. The SOCE inhibitor BTP2 blocked Ca2+ entry induced by naltriben but not by mibefradil. Thus, in HAT-7 cells, TRPM7 may serves both as a potential modulator of Orai-dependent Ca2+ uptake and as an independent Ca2+ entry pathway sensitive to pH. Therefore, TRPM7 may contribute directly to transepithelial Ca2+ transport in amelogenesis.

Analysis of upper threshold mechanisms of spherical neurons during extracellular stimulation

Exceeding a certain stimulation strength can prevent the generation of somatic action potentials, as has been demonstrated in vitro with extracellularly stimulated dorsal root ganglion cells as well as retinal ganglion cells. This phenomenon, termed upper threshold, is currently thought to be a consequence of sodium current reversal in strongly depolarized regions. Here we analyze the contribution of membrane kinetics, using spherical model neurons that are stimulated externally with a microelectrode, in more detail. During extracellular pulse application, the electric field depolarizes one part and hyperpolarizes the other part of the cell. Strong transmembrane currents are generated only in the active depolarized region, changing the overall polarization level. The asymmetric membrane voltage distribution caused by the stimulus strongly influences the cell’s behavior during and even after the stimulus. Effects on membrane voltage and transmembrane currents during and after the stimulus are shown and discussed in detail. Aside from the sodium current reversal, two more key mechanisms were identified in causing the upper threshold: strong potassium currents and inactivation of sodium channels. The contributions of the mechanisms involved strongly depend on cell properties, stimulus parameters, and other factors such as temperature. The conclusions presented here are based on several retinal ganglion cell models of the Fohlmeister group, a model with original Hodgkin-Huxley membrane, and a pyramidal cell model. NEW & NOTEWORTHY The upper threshold phenomenon in extracellular stimulation is analyzed in detail for spherical cells. Three main mechanisms were identified that prevent the generation of action potentials at high stimulation strengths: 1) strong potassium currents, 2) inactivating sodium ion channels, and 3) sodium current reversal. Ion channel kinetics in retinal ganglion cells, pyramidal cells, and the original Hodgkin-Huxley model were investigated under the influence of an extracellular stimulus.

A thermodynamic description for physiological transmembrane transport

A general formulation for both passive and active transmembrane transport is derived from basic thermodynamical principles. The derivation takes into account the energy required for the motion of molecules across membranes, and includes the possibility of modeling asymmetric flow. Transmembrane currents can then be described by the general model in the case of electrogenic flow. As it is desirable in new models, it is possible to derive other well known expressions for transmembrane currents as particular cases of the general formulation. For instance, the conductance-based formulation for current turns out to be a linear approximation of the general formula for current. Also, under suitable assumptions, other formulas for current based on electrodiffusion, like the constant field approximation by Goldman, can also be recovered from the general formulation. The applicability of the general formulations is illustrated first with fits to existing data, and after, with models of transmembrane potential dynamics for pacemaking cardiocytes and neurons. The general formulations presented here provide a common ground for the biophysical study of physiological phenomena that depend on transmembrane transport.

A thermodynamic description for physiological transmembrane transport

A generic formulation for both passive and active transmembrane transport is derived from basic thermodynamical principles. The derivation takes into account the energy required for the motion of molecules across membranes, and includes the possibility of modeling asymmetric flow. Transmembrane currents can then be described by the generic model in the case of electrogenic flow. As it is desirable in new models, it is possible to derive other well known expressions for transmembrane currents as particular cases of the generic formulation. For instance, the conductance-based formulation for current turns out to be a linear approximation of the generic current. Also, under suitable assumptions, other formulas for current based on electrodiffusion, like the constant field approximation by Goldman, can also be recovered from the generic formulation. The applicability of the generic formulations is illustrated first with fits to existing data, and after, with models of transmembrane potential dynamics for pacemaking cardiocytes and neurons. The generic formulations presented here provide a common ground for the biophysical study of physiological phenomena that depend on transmembrane transport.

A model for physiological transmembrane transport derived from thermodynamical principles

A generic formulation for both passive and active transmembrane transport is derived from basic thermodynamical principles. The derivation takes into account the energy required for the motion of molecules across membranes, and includes the possibility of modeling asymmetric flow. Transmembrane currents can then be described by the generic model in the case of electrogenic flow. As it is desirable in new models, it is possible to derive other well known expressions for transmembrane currents as particular cases of the generic formulation. For instance, the conductance-based formulation for current turns out to be a linear approximation of the generic current. Also, under suitable assumptions, other formulas for current based on electrodiffusion, like the constant field approximation by Goldman, can also be recovered from the generic formulation. The applicability of the generic formulations is illustrated first with fits to existing data, and after, with models of transmembrane potential dynamics for pacemaking cardiocytes and neurons. The generic formulations presented here provide a common ground for the biophysical study of physiological phenomena that depend on transmembrane transport.