Glia-neuron interactions underlie state transitions to generalized seizures

Abstract

Brain activity and connectivity alter drastically during epileptic seizures. Throughout this transition, brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state, spreading across the brain. It is, however, less clear which mechanisms underlie these state transitions. By studying neuronal and glial activity across the zebrafish brain, we observed striking differences between these networks. During the preictal period, neurons displayed a small increase in synchronous activity only locally, while the entire glial network was highly active and strongly synchronized across large distances. We observed that the transition from a preictal state to a generalized seizure leads to an abrupt increase in neuronal activity and connectivity, which is accompanied by a strong functional coupling between glial and neuronal networks. Optogenetic activation of glia induced strong and transient burst of neuronal activity, emphasizing a potential role for glia-neuron connections in the generation of epileptic seizures. Centre for the Unknown, Lisbon, Portugal) and H. Baier (MPI, Martinsried, Germany) for transgenic lines, T. Ohshima (Waseda university, Tokyo, Japan) for the GFAP:Gal4 plasmid. We thank M. Andresen, V. Nguyen and our fish facility support team for technical assistance. We also thank E. Brodtkorb (St Olav's University Hospital and NTNU) and the Yaksi lab members for stimulating discussions.

Glia Accumulate Evidence that Actions Are Futile and Suppress Unsuccessful Behavior

“…In the hippocampus, astrocytes can be intermediates between cholinergic input and interneurons (Pabst et al, 2016). Glial cells in zebrafish are activated before and during generalized seizures (Verdugo et al, 2019). These and other studies (Adamsky et al, Ding et al, 2013;Paukert et al, 2014; Poskanzer and Yuste, 2016; Srinivasan et al, 2015) point to an integrated role for astrocytes in information processing in brain circuits.…”

“…They can, in turn, influence other neurons through multiple mechanisms (Bazargani and Attwell, 2016), such as transmitter release (Araque et al, 2014) or modulation of extracellular potassium concentration (Haydon and Nedergaard, 2014;Wang et al, 2015). They play a role in controlling the states of neural networks, perform spatial and temporal integration, and can underlie slow shifts in brain states (Araque et al, 2014) like sleep and seizures (Kjaerby et al, 2017;Verdugo et al, 2019). Calcium signals in astrocytes are triggered by sensory input and behavior (Bekar et al, 2008;Ma et al, 2016;Paukert et al, 2014;Schummers et al, 2008;Srinivasan et al, 2015;Verkhratsky et al, 1998).…”

Radial glia in the zebrafish brain: Functional, structural, and physiological comparison with the mammalian glia

“…In fact, mice lacking the glutamate transporter EAAT2 exhibit epileptic seizures due to excessive glutamate (Tanaka et al, 1997). In line with this, breakdown of astroglia‐neuron interactions during epileptic seizures in zebrafish coincide with an excessive glutamate release (Diaz Verdugo et al, 2019).…”

Functional properties of habenular neurons are determined by developmental stage and sequential neurogenesis

“…One possibility is that early spontaneous activity might be driven by glia (Zhang et al, 2019) or other support cells (Babola et al, 2018), which usually generate slow bursts of activity. In fact, it was previously shown that astrocytes can modulate the bursting activity in the rodent habenula and astroglia activation in zebrafish can excite nearby neurons (Verdugo et al, 2019). Alternatively, it is possible that as the habenula develops, synaptic connections between habenular neurons become more mature.…”

“…Every recording was manually checked for motion and corresponding frames were discarded from further analysis. Individual neurons were semi-automatically detected using a pattern recognition as previously described (Jetti et al, 2014;Reiten et al, 2017;Verdugo et al, 2019). Once neurons were detected, their locations were individually tracked during the recording.…”