Elevated extracellular potassium ion concentrations suppress hippocampal oscillations in a mouse model of Dravet syndrome in-vitro

Abstract

Background: Hippocampal hyperexcitability and seizure-like events have been consistently demonstrated in hippocampal slice preparations perfused with ≥ 5 mM high [K + ] artificial cerebrospinal fluid (ACSF). Accordingly, high [K + ] ACSF has been effectively employed as ionic model of seizure for in vitro experiments, but then, how reliable is this model when employed for in-vitro studies of brain tissues with dysregulated K + homeostasis? To address this question, we examined how elevations of [K + ]o affect hippocampal oscillations in Scn1a mutant mouse, a mouse model of Dravet syndrome, a devastating genetic-epilepsy associated with gliosis, a major cause of dysregulated K + homeostasis in epileptic brain. Methods: To this end, performing local field potential (LFP) recordings from hippocampi of P30 to P38 Scn1a mutant mice ( Scn1a +/- ) and wild-type littermates ( Scn1a +/+ ), maintained on a C57BL/6 genetic background, in brain slice preparations in normal and high K + conditions, we studied the effect of 4 mM and 5 mM high [K + ] ACSF(s) on hippocampal oscillations. Results: Hippocampal hyperexcitability was observed only in Scn1a +/+ but not in Scn1a +/- mice. In Scn1a +/- mice, spontaneous hippocampal hyperexcitability was observed in normal ACSF but was significantly suppressed by 4 mM and 5 mM high [K + ] ACSF(s). Conclusion: In conclusion, these findings, for the first time, provide evidence of spontaneous hippocampal activity in Scn1a +/- mice older than P30 which may be potentially used as a target for screening anti-epileptic approaches, beneficial for the treatment of DS. Elevated [K + ] o- induced depolarization block of neuronal action potentials is involved in epileptic brain tissues modulated in elevated [K + ] o . This mechanism underlies the suppressing effect of high [K + ] ACSF on hippocampal oscillations in Scn1a +/- mice in vitro . Future studies employing the high K + ionic model for studies of epileptic brain tissues are required to determine how K + homeostasis is handled by neurons and glial cells in epileptic brain tissues. Keywords: Dravet syndrome, artificial cerebrospinal fluid (ACSF), Scn1a mutant mouse, depolarization block