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