Experimentally Induced Convulsive Seizures Are Modulated in Part by Zinc Ions through the Pharmacoresistant Ca_v2.3 Calcium Channel

Background/aims: Still in 1999 the first hints were published for the pharmacoresistant Ca_v2.3 calcium channel to be involved in the generation of epileptic seizures, as transcripts of alpha1E (Ca_v2.3) and alpha1G (Ca_v3.1) are changed in the brain of genetic absence epilepsy rats from Strasbourg (GAERS). Consecutively, the seizure susceptibility of mice lacking Ca_v2.3 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, Ca_v2.3-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 Ca_v2.3-competent but increases it in Ca_v2.3-deficient mice. In vivo, Ca_v2.3 must be under tight control by endogenous trace metal cations (Zn²⁺ and Cu²⁺). The dyshomeostasis of either of them, especially of Cu²⁺, may alter the regulation of Ca_v2.3 severely and its activity for Ca²⁺ 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 Zn²⁺. As the blood-brain barrier limits the distribution of bioavailable Zn²⁺ or Cu²⁺ into the brain, we administered micromolar Zn²⁺ 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 Ca_v2.3-competent mice than in KO mice and histidine lessens seizure severity in competent but not in Ca_v2.3-deficient mice. Surprisingly, Zn²⁺ plus histidine resembles the kainate only control with more seizure severity in Ca_v2.3-competent than in deficient mice.

Conclusion: Ca_v2.3 represents one important Zn²⁺-sensitive target, which is useful for modulating convulsive seizures.