Connexin 43 Differentially Regulates Epileptiform Activity in Models of Convulsive and Non-convulsive Epilepsies.

Renáta Vincze,Zsolt Kovács,Zsolt Szabó,Julianna Kardos,László Héja,Márton Péter

doi:10.3389/fncel.2019.00173

Abstract

The influence of astrocytic cell networks on neuronal network activity is an emerging issue in epilepsy. Among the various mechanisms by which astrocytes modulate neuronal function, synchronization of astrocytes via gap junction channels is widely considered to be a crucial mechanism in epileptic conditions, contributing to the synchronization of the neuronal cell networks, possibly inducing recurrent epileptiform activity. Here, we explored whether modulation of astrocytic gap junctions could alter epileptic seizures in different types of epilepsy. Opening of gap junctions by trimethylamine intensifies seizure-like events (SLEs) in the low-[Mg2+] in vitro model of temporal lobe epilepsy, while alleviates seizures in the in vivo WAG/Rij rat model of absence epilepsy. In contrast, application of the gap junction blocker carbenoxolone prevents the appearance of SLEs in the low-[Mg2+] epilepsy model, but aggravates seizures in non-convulsive absence epilepsy, in vivo. Pharmacological dissection of neuronal vs. astrocytic connexins shows that astrocytic Cx43 contribute to seizure formation to a significantly higher extent than neuronal Cx36. We conclude that astrocytic gap junctions are key players in the formation of epileptiform activity and we provide a scheme for the different mode of action in the convulsive and non-convulsive epilepsy types.

Highlights

Epilepsy is one of the most common neurological disorder affecting 1–2% of the population worldwide
We monitored the contribution of astrocytic gap junction channels to in vitro epileptiform activity in the CA3 region of juvenile rat acute hippocampal slices in the low-Mg2+ in vitro epilepsy model
Recurrent seizure-like events (SLEs) have been characterized by paroxysmal depolarization shifts before the onset of SLEs appeared in the presence of lowMg2+ Artificial cerebrospinal fluid (ACSF) (Figure 1A)

Summary

Introduction

Epilepsy is one of the most common neurological disorder affecting 1–2% of the population worldwide. In addition to classical functions, like K+ buffering through Na+/K+ pumps, Na+/K+/Cl− cotransporters and Kir channels (Kofuji and Newman, 2004; Wallraff et al, 2006; Seifert et al, 2009; Bedner and Steinhäuser, 2013; Mukai et al, 2018), water regulation by aquaporin-4 channel (Binder et al, 2012; Hubbard et al, 2015) as well as glutamate uptake via two astrocytic excitatory amino acid transporter subtypes, EAAT1 and EAAT2 (Watanabe et al, 1999; Héja, 2014; Eid et al, 2018), astrocytes can directly modulate synaptic activity They can dynamically interact with neurons by releasing various neurotransmitters (Glu, GABA, D-serine, ATP) in response to intracellular Ca2+ concentration changes triggered by ionotropic and metabotropic receptor activation (Seifert et al, 2009; Héja, 2014; Steinhäuser et al, 2016; Robin et al, 2018). Astrocytes can even turn glutamatergic excitation into tonic inhibition by the Glu/GABA exchange mechanism (Héja et al, 2009, 2012)

Objectives

Methods

Results

Conclusion