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Neurostimulation is an emerging treatment for drug-resistant epilepsies when surgery is contraindicated. Recent clinical results demonstrate significant seizure frequency reduction in epileptic patients, however the mechanisms underlying this therapeutic effect are largely unknown. This study aimed at gaining insights into local direct current stimulation (LDCS) effects on hyperexcitable tissue, by i) analyzing the impact of electrical currents locally applied on epileptogenic brain regions, and ii) characterizing currents achieving an "anti-epileptic" effect (excitability reduction). First, a neural mass model of hippocampal circuits was extended to accurately reproduce the features of hippocampal paroxysmal discharges (HPD) observed in a mouse model of epilepsy. Second, model predictions regarding current intensity and stimulation polarity were confronted to in vivo mice recordings during LDCS (n = 8). The neural mass model was able to generate realistic hippocampal discharges. Simulation of LDCS in the model pointed at a significant decrease of simulated HPD (in duration and occurrence rate, not in amplitude) for cathodal stimulation, which was successfully verified experimentally in epileptic mice. Despite the simplicity of our stimulation protocol, these results contribute to a better understanding of clinical benefits observed in epileptic patients with implanted neurostimulators. Our results also provide further support for model-guided design of neuromodulation therapy.

Epilepsy is a neurological disorder characterized by recurrent seizures which affects about 1% people worldwide. During the past decades, some mechanisms involved in ictogenesis (generation of seizures) have been identified and, to some extent, partially understood. However, regarding epileptogenesis (process by which a neuronal system becomes epileptic), underlying mechanisms remain elusive. This difficulty is mostly related to the fact that epileptogenesis can only be addressed using experimental models. In this study, we have analyzed the shape of a specific electrophysiological pattern, referred to as "epileptic spike", encountered during the epileptogenesis process in an in vivo model of temporal lobe epilepsy (mouse, kainate). Results show that the features of these transient events (duration and amplitude) change as a function of time as the brain evolves towards the chronic epileptic state characterized by the appearance of spontaneous seizures. Using a detailed computational model of the hippocampus (CA1 sub-field), an interpretation of observed modifications is provided, in relationship with possible alterations that take place in underlying neuronal circuits.

Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiological, cellular and molecular mechanisms inducing post-ischemic plasticity of NMDA receptors, focusing on the sensitive CA1 pyramidal neurons in the hippocampus as compared to the relatively resistant neighboring CA3 neurons. Both a change in the equilibrium between protein tyrosine kinases/phosphatases and an increased density of surface NMDA receptors in response to ischemia may explain the selective vulnerability of specific cell types. Implications for the treatment of stroke and reasons for the failures of human clinical trials utilizing NMDA receptor antagonists are also discussed.

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 on I(Ba). 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 microM BAPTA-AM or 10 mM EGTA). Quite unexpectedly, blockade of the P/Q-like (omega-Aga WA-sensitive) component of the calcium current by 500 nM of omega-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 on I(Ba), isradipine, nifedipine, and omega-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 omega-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 (omega-Aga WA-sensitive) calcium channels in these processes is discussed.