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While electrical stimulation of brain tissue has been thoroughly investigated over the last decades, ongoing questions remain regarding the neurophysiological effects of low-level electric fields (on the order of 1 V/m) on brain activity. Electric fields at such levels are, for example, induced by transcranial direct/alternating current stimulation (tDCS/tACS). Action potentials can be indeed elicited when applied (supra-threshold) electric fields are in the 10–100 V/m range, while lower (sub-threshold) electric fields result in more limited and subtler membrane polarization effects. In this review, we address the question of the mechanisms underlying the immediate effects (also referred to as acute, concurrent or short-term) and the lasting effects (also referred to as long-term or after-effects) of low-level electric fields on brain tissue. We review recent evidence at the in vitroand in vivo(animal and human) level, and also present mechanistic insights gained from in silicomodels, which are still few but have received increased attention over the recent past years. We highlight the convergent evidence towards potential mechanisms, and also discuss discrepancies between in vitrostudies and human tDCS/tACS studies that require further investigation to bridge the gap between the single-cell and large-scale network level. Possible novel avenues of research are discussed.

For efficient information processing during cognitive activity, functional brain networks have to rapidly and dynamically reorganize on a sub-second time scale. Tracking the spatiotemporal dynamics of large scale networks over this short time duration is a very challenging issue. Here, we tackle this problem by using dense electroencephalography (EEG) recorded during a picture naming task. We found that (i) the picture naming task can be divided into six brain network states (BNSs) characterized by significantly high synchronization of gamma (30–45 Hz) oscillations, (ii) fast transitions occur between these BNSs that last from 30 msec to 160 msec, (iii) based on the state of the art of the picture naming task, we consider that the spatial location of their nodes and edges, as well as the timing of transitions, indicate that each network can be associated with one or several specific function (from visual processing to articulation) and (iv) the comparison with previously-used approach aimed at localizing the sources showed that the network-based approach reveals networks that are more specific to the performed task. We speculate that the persistence of several brain regions in successive BNSs participates to fast and efficient information processing in the brain.

L’ischémie cérébrale transitoire induit une mort neuronale retardée de certains types cellulaires et régions cérébrales mais épargne des neurones d’autres territoires. Un processus clé par lequel la privation d’oxygène et de glucose déclenche la mort cellulaire est l’accumulation excessive de glutamate menant à une hyperexcitabilité neuronale. Cet article propose une mise à jour des connaissances sur les mécanismes neurophysiologiques cellulaires et moléculaires générant la plasticité post-ischémique des récepteurs NMDA. Nous la focaliserons sur l’étude des neurones pyramidaux CA1 vulnérables comparés aux neurones résistants de la région voisine CA3 au sein de l’hippocampe. Les modulations spécifiques des récepteurs NMDA pourraient expliquer la vulnérabilité sélective de certains types neuronaux. Les implications de ces mécanismes dans le traitement des attaques cérébrales et les raisons de l’échec de l’utilisation des antagonistes des récepteurs NMDA dans les essais cliniques humains sont également discutées.

In CA3 pyramidal neurons from organotypic slice cultures, activation of Gq‐coupled group I metabotropic glutamate receptors (mGluRs) induces a non‐selective cationic conductance that enhances excitability. We have found that this response shares several properties with conductances that are mediated by the transient receptor potential (TRP) family of ion channels, including inhibition by La3+, 2‐aminoethoxydiphenylborane (2APB), cis‐N‐(2‐phenylcyclopentyl)azacyclotridec‐1‐en‐2‐amine (MDL 12,330A) and a doubly rectifying current‐voltage relationship. Stimulation of mGluR1 and mGluR5 converged to activate the TRP‐like conductance in a synergistic manner, and activation of either subtype alone produced only a fraction of the normal response. Activation of the cationic current required elevated intracellular Ca2+. Chelating intracellular Ca2+or blocking Ca2+entry through voltage‐gated Ca2+channels attenuated responses to the activation of mGluRs. Conversely, raising intracellular Ca2+potentiated mGluR activation of the TRP‐like conductance. Under control conditions, blocking G protein activation using intracellular GDPβS with or without N‐(2, 6‐dimethylphenylcarbamoylmethyl) triethylammonium chloride (QX‐314) prevented mGluR‐mediated activation of the TRP‐like conductance. Following G protein blockade, however, the coupling between mGluRs 1 and/or 5 and the TRP‐like conductance was rescued by increasing intracellular Ca2+. This suggests that a G protein‐independent signalling pathway is also activated by group I mGluRs. Such a pathway may represent an alternative transduction mechanism to maintain metabotropic responses under conditions where G proteins are functionally uncoupled from their cognate receptors.

The contribution of voltage-gated calcium channels (VGCC) to the development of cultured embryonic cockroach brain neurons was assessed using pharmacological agents. VGCC currents were recorded using the patch-clamp technique and were found to be blocked dose-dependently by micromolar concentrations of mibefradil. The activation and inactivation properties of the calcium channels enable a sizeable calcium current to flow at rest (about −30 and −20 mV in high-potassium culture media). As expected, the cytoplasmic-free calcium concentration was found to rise when the extracellular potassium concentration was raised from 3 to 15 and 30 mM. The effects of VGCC blockers and calcium chelators were different in fresh and in mature cultures in which the neurons were connected to each other to form a defined network. In fresh cultures, the two non-selective VGCC blockers (verapamil and mibefradil) induced a dose-dependent cell death that was proportional to their blocking effect onIBa. This effect could not be prevented by addition of fetal calf serum to the culture medium. A similar effect was obtained using intra- or extracellular calcium chelating agents (10 μM BAPTA-AM or 10 mM EGTA). Quite unexpectedly, blockade of the P/Q-like (ω-Aga WA-sensitive) component of the calcium current by 500 nM of ω-AgaTx IVA had no lethal effect, suggesting that the corresponding channels are not involved in the survival mechanism. As expected from their lack of effect onIBa, isradipine, nifedipine, and ω-CgTx GVIA did not induce cell death. When the neurons started growing neurites, their sensitivity to calcium channel blockade by mibefradil decreased, indicating a correlation between neurite outgrowth and resistance to calcium depletion. In mature cultures, the neurons became resistant to mibefradil, verapamil, and BAPTA-AM. However, these agents, as well as ω-AgaTx IVA, had a significant inhibitory effect on the increase in diameter of the connectives that linked adjacent clusters of neurons. This effect has been shown to result, in the case of mibefradil, from an inhibition of neurite outgrowth characterized by a significant reduction of the number of primary neurites and secondary branchings but not to a significant modification of the diameter of individual neurites. These results support the view that, as in vertebrates, calcium influx through VGCC plays an important role in survival and neurite outgrowth of cultured embryonic insect neurons. The differential contribution of the P/Q-like and R-like (ω-Aga WA-sensitive) calcium channels in these processes is discussed.

By means of the whole cell patch-clamp technique, the biophysical and pharmacological properties of voltage-dependent Ba2+currents (IBa) were characterized in embryonic cockroach brain neurons in primary culture.IBawas characterized by a threshold of approximately −30 mV, a maximum at ∼0 mV, and a reversal potential near +40 mV. Varying the holding potential from −100 to −40 mV did not modify these properties. The steady-state, voltage-dependent activation and inactivation properties of the current were determined by fitting the corresponding curves with the Boltzmann equation and yielded V0.5of −10 ± 2 (SE) mV and −30 ± 1 mV, respectively. IBawas insensitive to the dihydropyridine (DHP) agonist BayK8644 (1 μM) and antagonist isradipine (10 μM) but was efficiently and reversibly blocked by the phenylalkylamine verapamil in a dose-dependent manner (IC50= 170 μM). The toxin ω-CgTxGVIA (1 μM) had no significant effect on IBa. Micromolar doses of ω-CmTxMVIIC were needed to reduce the current amplitude significantly, and the effect was slow. At 1 μM, 38% of the peak current was blocked after 1 h. In contrast, IBawas potently and irreversibly blocked by nanomolar concentrations of ω-AgaTxIVA in ∼81% of the neurons. Approximately 20% of the current was unaffected after treatment of the neurons with high concentrations of the toxin (0.4–1 μM). The steady-state dose-response relationship was fitted with a Hill equation and yielded an IC50of 17 nM and a Hill coefficient (n) of 0.6. A better fit was obtained with a combination of two Hill equations corresponding to specific (IC50= 9 nM; n =1) and nonspecific (IC50= 900 nM; n =1) ω-AgaTxIVA–sensitive components. In the remaining 19% of the neurons, concentrations ≥100 nM ω-AgaTxIVA had no visible effect on IBa. On the basis of these results, it is concluded that embryonic cockroach brain neurons in primary culture express at least two types of voltage-dependent, high-voltage–activated (HVA) calcium channels: a specific ω-AgaTxIVA–sensitive component and DHP-, ω-CgTxGVIA–, and ω-AgaTxIVA–resistant component related respectively to the P/Q- and R-type voltage-dependent calcium channels.

By means of the whole cell patch-clamp technique, the biophysical and pharmacological properties of voltage-dependent Ba²⁺ currents (IBa) were characterized in embryonic cockroach brain neurons in primary culture. IBa was characterized by a threshold of approximately −30 mV, a maximum at ~0 mV, and a reversal potential near +40 mV. Varying the holding potential from −100 to −40 mV did not modify these properties. The steady-state, voltage-dependent activation and inactivation properties of the current were determined by fitting the corresponding curves with the Boltzmann equation and yielded V0.5 of −10 ± 2 (SE) mV and −30 ± 1 mV, respectively. IBa was insensitive to the dihydropyridine (DHP) agonist BayK8644 (1 μM) and antagonist isradipine (10 μM) but was efficiently and reversibly blocked by the phenylalkylamine verapamil in a dose-dependent manner (IC50 = 170 μM). The toxin ω-CgTxGVIA (1 μM) had no significant effect on IBa. Micromolar doses of ω-CmTxMVIIC were needed to reduce the current amplitude significantly, and the effect was slow. At 1 μM, 38% of the peak current was blocked after 1 h. In contrast, IBa was potently and irreversibly blocked by nanomolar concentrations of ω-AgaTxIVA in ~81% of the neurons. Approximately 20% of the current was unaffected after treatment of the neurons with high concentrations of the toxin (0.4-1 μM). The steady-state dose-response relationship was fitted with a Hill equation and yielded an IC50 of 17 nM and a Hill coefficient (n) of 0.6. A better fit was obtained with a combination of two Hill equations corresponding to specific (IC50 = 9 nM; n = 1) and nonspecific (IC50 = 900 nM; n = 1) ω-AgaTxIVA-sensitive components. In the remaining 19% of the neurons, concentrations ≥100 nM ω-AgaTxIVA had no visible effect on IBa. On the basis of these results, it is concluded that embryonic cockroach brain neurons in primary culture express at least two types of voltage-dependent, high-voltage-activated (HVA) calcium channels: a specific ω-AgaTxIVA-sensitive component and DHP-, ω-CgTxGVIA-, and ω-AgaTxIVA-resistant component related respectively to the P/Q- and R-type voltage-dependent calcium channels.