Abstracts

Rationale: The transitions from normal brain activity to a generalized seizure are dramatic, and may lead to brain damage or even death. However, it is unclear how local oscillatory neuronal activity leads to sudden bursts of generalized neuronal activity invading the entire brain, often crossing boundaries between brain regions. Neuron-glia interactions are proposed to be important for seizure generation, especially due to the direct role of astrocytes for the regulation of neuronal excitability and synaptic transmission. It is, however, less clear how such interactions between neurons and glia underlie state transitions of neuronal networks leading to generalized seizures.  Methods: To address this, we studied pharmacologically induced seizures in the zebrafish model. We performed in depth analysis of the activity of thousands of individual neurons and glia across the zebrafish brain.  Results: Our findings suggest that while the number of active neurons increases preceding generalized seizures, the activity levels of active neurons remain unaffected. Moreover, our data suggest that the synchrony of the brain network increases within and across brain regions, during the period preceding the generalized seizures. Finally, we found that the transition from a local oscillatory state to a generalized seizure is abrupt and cannot be explained by the gradual changes of the network connectivity and synchrony. Instead, we observed that the explosion of network activity and the initiation of generalized seizures corresponds to a period where glial activity reaches its peak and neuron-glia networks are highly synchronized. Finally, we showed that glial activity strongly modulates the neuronal activity. Conclusions: Hence, we propose that changing homeostatic interactions across neuron-glia networks is a potential mechanism for the manifestation of generalized seizures. Funding: This research is funded by The Liaison Committee for Education, Research and Innovation in Central Norway, ‘Samarbeidsorganet’ Grant (SMS, NJY, EY), Flanders Science Foundation Grant (CDV,EY), and ERC Starting Grant (CD,RP,EY). We declare no competing financial interest.