Glia-neuron interactions underlie state transitions to generalized seizures

Carmen Diaz Verdugo,Evelien Van Hoeymissen,Akira Muto,Celine Deneubourg,Robbrecht Pelgrims,Silke Vanderhaeghe,Mehmet Ilyas Cosacak,Ecem Aydin,Nathalie Jurisch-Yaksi,Sverre Myren-Svelstad,Caghan Kizil,Emre Yaksi,Koichi Kawakami,Julie Vancraeynest

doi:10.1038/s41467-019-11739-z

Abstract

Brain activity and connectivity alter drastically during epileptic seizures. The brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state. It is, however, less clear which mechanisms underlie the state transitions. By studying neural and glial activity in zebrafish models of epileptic seizures, we observe striking differences between these networks. During the preictal period, neurons display a small increase in synchronous activity only locally, while the gap-junction-coupled glial network was highly active and strongly synchronized across large distances. The transition from a preictal state to a generalized seizure leads to an abrupt increase in neural activity and connectivity, which is accompanied by a strong alteration in glia-neuron interactions and a massive increase in extracellular glutamate. Optogenetic activation of glia excites nearby neurons through the action of glutamate and gap junctions, emphasizing a potential role for glia-glia and glia-neuron connections in the generation of epileptic seizures.

Highlights

Brain activity and connectivity alter drastically during epileptic seizures
We propose that alterations in glia-neuron interactions underlie state transitions that lead to generalized epileptic seizures
Previous reports have shown that electrical activity can be reliably measured by local field potential (LFP) recordings at high frequency with a micro-electrode inserted in the midbrain[24,25]

Summary

Introduction

Brain activity and connectivity alter drastically during epileptic seizures. The brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state. How glia-neuron interactions are involved in initiation and propagation of epileptic seizures remains an open question with potential therapeutic applications To address this question, we characterized the state transitions of neural and glial activity and connectivity in pharmacological-induced seizure models of zebrafish larvae[24,25,26]. We show that during the preictal state, the neural synchrony increases only locally, while the gap junction coupled glial networks are activated and synchronized across large distances, independent of neural activity and synchrony. We show that activation of glial networks leads to a strong increase in neural activity through the action of glutamate and gap junctions Taken together, these interactions could underlie the rapid transition from a preictal state to a generalized seizure, which goes beyond neural connectivity rules. We propose that alterations in glia-neuron interactions underlie state transitions that lead to generalized epileptic seizures

Methods

Results

Conclusion