How Epilesy Changes Sodium Channels.

Abstract

Induction of Neonatal Sodium Channel II and III α-Isoform mRNAs in Neurons and Microglia After Status Epilepticus in the Rat Hippocampus Aronica E, Yankaya B, Troost D, van Vliet EA, Lopes da Silva FH, Gorter JA Eur J Neurosci 2001;13(6):1261 Sodium channels (NaChs) regulate neuronal excitability in both physiologic and pathological conditions, including epilepsy, and are therefore an important target for antiepileptic drugs (AEDs). In the present study, we examined the distribution of messenger RNAs (mRNAs) encoding neonatal NaChs II and III α-isoforms in control rat hippocampus and after electrically induced status epilepticus (SE), with nonradioactive in situ hybridization (ISH). Only weak expression of neonatal NaCh II and III mRNAs was observed in control hippocampus. By contrast, increased expression of neonatal NaCh II and III mRNAs was observed 4 hours after the induction of SE in neurons of CA1–CA3 and the dentate granule cell layer. These changes were detected only in rats in which SE was successfully induced and persisted, although less intensely, for up to 3 months, when rats display spontaneous seizures. Strong expression of neonatal NaCh α-isoforms was observed 1 week after SE in microglial cells, as confirmed by double labeling, combining ISH with immunocytochemistry for microglia markers. The increased expression of neonatal isoforms of the NaCh in both neurons and microglial cells may represent a critical mechanism for modulation of neuronal excitability, glial function, and pharmacologic response to AEDs in the course of epileptogenesis. Sodium Currents in Isolated Rat Ca1 Pyramidal and Dentate Granule Neurones in the Post-Status Epilepticus Model of Epilepsy Ketelaars SOM, Gorter JA, van Vliet EA, Lopes da Silva FH, Wadman WJ Neuroscience 2001;105:109–120 Status epilepticus (SE) was induced in the rat by long-lasting electrical stimulation of the hippocampus. After a latent period of 1 week, spontaneous seizures increased in frequency and severity in the following weeks, finally culminating after 3 months in a chronic epileptic state. In these animals, we determined the properties of voltage-dependent sodium currents in short-term isolated CA1 pyramidal neurons and dentate granule (DG) cells by using the whole-cell voltage-clamp technique. The conductance of the fast transient sodium current was larger in SE rats (84 ± 7 nS vs 56 ± 6 nS) but related to a difference in cell size, so that the neurons had a similar specific sodium conductance (control, 7.8 ± 0.8 nS/pF; SE, 6.7 ± 0.8 nS/pF). Current activation and inactivation were characterized by a Boltzmann function. After SE, the voltage dependence of activation was shifted to more negative potentials (control, −45.1 ± 1.4 mV; SE, −51.5 ± 2.9 mV; P < 0.05). In combination with a small shift in the voltage dependence of inactivation to more depolarized potentials (control, −68.8 ± 2.3 mV; SE, −66.3 ± 2.3 mV), it resulted in a window current that was much increased in the SE neurons (median, 64 pA in control; 217 pA in SE; P < 0.05). The peak of this window current shifted to more hyperpolarized potentials (control, −44 mV; SE, −50 mV; P < 0.05). No differences were found in the sodium currents analyzed in DG cells of control and SE animals. The changes observed in CA1 neurons after SE contribute to enhanced excitability, in particular, when membrane potential is near firing threshold. They can, at least partly, explain the lower threshold for epileptic activity in SE animals. The comparison of CA1 with DG neurons in the same rats demonstrates a differential response in the two cell types that participated in very similar seizure activity.