Microglia mitigate neuronal activation in a zebrafish model of Dravet syndrome
La microglie atténue l'activation neuronale dans un modèle de poisson zèbre du syndrome de Dravet
Résumé
It has been known for a long time that epileptic seizures induce brain neuroinflammation through microglia activation. Nevertheless, these cells have not yet received the attention they deserve in epilepsy research and the consequences of this microglial response on subsequent neuronal activity remain poorly understood. Here, we sought to fill this gap and gain a larger understanding of the role of microglia in the pathophysiology of epilepsy, using an established zebrafish Dravet syndrome epilepsy model based on Scn1Lab sodium channel loss-of-function, combined with live microglia and neuronal Ca2+ imaging, local field potential (LFP) recording and genetic microglial ablation. First, in scn1Lab-deficient larvae experiencing epileptiform seizures, microglia displayed morphological and biochemical features suggesting M1-like pro-inflammatory activation, including reduced branching, amoeboid-like morphology, and a marked increase in the number of microglia expressing pro-inflammatory cytokine Il1β. More importantly, scn1Lab-KD larvae fully lacking microglia showed a significantly increased neuronal activation compared to that seen in scn1Lab-KD individuals with microglia, as shown by LFP recording and Ca2+ imaging, and also by the epileptiform seizure-related whirling swimming of larvae. These findings are evidence that despite a microglial activation and the synthesis of pro-inflammatory cytokines, microglia provide neuroprotection to epileptic neuronal networks, making these cells a promising therapeutic target in epilepsy.
Domaines
Neurobiologie
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