Experimentally Induced Convulsive Seizures Are Modulated in Part by Zinc Ions through the Pharmacoresistant Ca2.3 Calcium Channel.

BACKGROUND/AIMS: Still in 1999 the first hints were published for the pharmacoresistant Ca2.3 calcium channel to be involved in the generation of epileptic seizures, as transcripts of alpha1E (Ca2.3) and alpha1G (Ca3.1) are changed in the brain of genetic absence epilepsy rats from Strasbourg (GAERS). Consecutively, the seizure susceptibility of mice lacking Ca2.3 was analyzed in great detail by using 4-aminopyridine, pentylene-tetrazol, N-methyl-D-aspartate and kainic acid to induce experimentally convulsive seizures. Further, γ-hydroxybutyrolactone was used for the induction of non-convulsive absence seizures. For all substances tested, Ca2.3-competent mice differed from their knockout counterparts in the sense that for convulsive seizures the deletion of the pharmacoresistant channel was beneficial for the outcome during experimentally induced seizures [1]. The antiepileptic drug lamotrigine reduces seizure activity in Ca2.3-competent but increases it in Ca2.3-deficient mice. In vivo, Ca2.3 must be under tight control by endogenous trace metal cations (Zn and Cu). The dyshomeostasis of either of them, especially of Cu, may alter the regulation of Ca2.3 severely and its activity for Ca conductance, and thus may change hippocampal and neocortical signaling to hypo- or hyperexcitation.

METHODS

To investigate by telemetric EEG recordings the mechanism of generating hyperexcitation by kainate, mice were tested for their sensitivity of changes in neuronal (intracerebroventricular) concentrations of the trace metal cation Zn. As the blood-brain barrier limits the distribution of bioavailable Zn or Cu into the brain, we administered micromolar Zn ions intracerebroventricularly in the presence of 1 mM histidine as carrier and compared the effects on behavior and EEG activity in both genotypes.

RESULTS

Kainate seizures are more severe in Ca2.3-competent mice than in KO mice and histidine lessens seizure severity in competent but not in Ca2.3-deficient mice. Surprisingly, Zn plus histidine resembles the kainate only control with more seizure severity in Ca2.3-competent than in deficient mice.

CONCLUSION

Ca2.3 represents one important Zn-sensitive target, which is useful for modulating convulsive seizures.