Seizure-induced increase in microglial cell population in the developing zebrafish brain#

Authors#

Teresa G. Martinsa, Remon Soliman, Maria Lorena Cordero-Maldonado, Cristina Donato, Corrado Ameli, Laurent Mombaerts, Alexander Skupina, Francesca Peri, Alexander D. Crawford

Abstract#

Epilepsy is a chronic brain disorder characterized by unprovoked and recurrent seizures, of which 60% are of unknown etiology. Recent studies implicate microglia in the pathophysiology of epilepsy. However, their role in this process, e.g. following early-life seizures, remains poorly understood in part due to the lack of suitable experimental models allowing the in vivo imaging of microglial activity using minimally-invasive techniques. Given the advantage of zebrafish larvae for such imaging approaches, we sought for the first time to describe the microglial responses after acute seizures in two different zebrafish larval models: a chemically-induced epileptic model by the systemic injection of kainate at 3 days post-fertilization, and the didys552 genetic epilepsy model, which carries a mutation in scn1lab that leads to spontaneous epileptiform discharges. Kainate-treated larvae exhibited a transient brain damage shown by increased numbers of apoptotic nuclei as early as one day post-injection, which was followed by increased numbers of microglia in the brain. A similar microglial phenotype was also observed in the didys552-/- mutants, indicating that microglia numbers change in response to seizure-like activity in the brain. Interestingly, kainate-treated larvae also displayed decreased seizure threshold to subsequent pentylenetetrazole-induced seizures, as shown by higher locomotor and encephalographic activity as compared to vehicle-injected larvae. These results are comparable to experimental kainate-induced rodent seizure models and suggest the suitability of the zebrafish seizure models for future studies, particularly to elucidate the links between the epileptogenesis and the microglial dynamic changes after seizure induction in the developing brain, and to understand how these modulate seizure susceptibility.