Kainic acid (KA)-induced seizures and other experimental models of epilepsy have been proven to be instrumental in identifying novel targets that could be responsible for human icto- and epileptogenesis. We have previously shown that the ablation of pharmacoresistant voltage-gated Ca2+ channels with Cav2.3 as central ion-conducting pore (R-type Ca2+ channel) reduces the sensitivity towards KA-induced epilepsy in mice. In vivo, Cav2.3 channels are thought to be under tight allosteric control by endogenous loosely bound trace metal cations (Zn2+ and Cu2+) that suppress channel gating via a high-affinity trace metal-binding site. Metal dyshomeostasis in the brain, which is a common feature of (KA-induced) seizures, could therefore alter the normal function of Cav2.3 channels and may shift hippocampal and neocortical signaling towards hyperexcitation. To investigate the role of loosely bound metal ions for KA-induced hyperexcitation in vivo, we examined the effects of manipulating brain trace metal homeostasis in mice. To this end, we developed a murine system for intracerebroventricular administration of trace metal ions and/or histidine (His), which can bind Zn2+ and Cu2+ and is involved in their transendothelial transport at the blood–brain barrier. Unexpectedly, our preliminary findings indicate that application of His alone but not in the presence of Zn2+ has substantial beneficial effects on the outcome of KA-induced epilepsy in mice. As such, our results emphasize previous findings on the complex, two-sided role of loosely bound metal ions with regard to neuronal excitation and degeneration under pathophysiological conditions.
Plastic cannulas Telemetry Trace metal cations Pharmacoresistant calcium channel R-type
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We would like to especially thank Mrs. Renate Clemens for her dedication and hard work in this project.
This study was funded by a DFG/German Research Foundation Grant (Schn 387/21-1 and /21-2).
Compliance with ethical standards
Conflict of interest
Part of this study was presented at Annual Meeting of the German and Austrian Society for Epileptology and the Swiss Epilepsy-Liga in Wien, May 3rd–6th, 2017. Dr. Maxine Dibué-Adjei is an Employee of LivaNova PLC. None of the authors has anything other to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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