Journal
EPILEPSIA
Volume 59, Issue 11, Pages 2061-2074Publisher
WILEY
DOI: 10.1111/epi.14576
Keywords
animal model; antiepileptic screening; GABA receptor; neurodevelopment; zebrafish
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Funding
- Savoy Foundation
- Fonds de Recherche Quebec Sante
- Dravet Canada
- Groupe de Recherche sur le Systeme Nerveux Central
- Quebec Ministere de l'Education, de l'Enseignement Superieur et de Recherche
- Research Center of the University of Montreal Hospital Center
- Rare Disease Model and Mechanism network
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Objective In humans, mutations of the gamma-aminobutyric acid receptor subunit 1 (GABRA1) cause either mild or severe generalized epilepsy. Although these epilepsy-causing mutations have been shown to disrupt the receptor activity in vitro, their in vivo consequences on brain development and activity are not known. Here, we aim at unraveling the epileptogenesis mechanisms of GABRA1 loss of function. Methods Results We generated a gabra1(-/-) zebrafish mutant line displaying highly penetrant epileptic seizures. We sought to identify the underlying molecular mechanisms through unbiased whole transcriptomic assay of gabra1(-/-) larval brains. Interestingly, mutant fish show fully penetrant seizures at juvenile stages that accurately mimic tonic-clonic generalized seizures observed in patients. Moreover, highly penetrant seizures can be induced by light stimulation, thus providing us with the first zebrafish model in which evident epileptic seizures can be induced by nonchemical agents. Our transcriptomic assay identified misregulated genes in several pathways essential for correct brain development. More specifically, we show that the early development of the brain inhibitory network is specifically affected. Although the number of GABAergic neurons is not altered, we observed a drastic reduction in the number of inhibitory synapses and a decreased complexity of the GABAergic network. This is consistent with the disruption in expression of many genes involved in axon guidance and synapse formation. Significance Together with the role of GABA in neurodevelopment, our data identify a novel aspect of epileptogenesis, suggesting that the substratum of GABRA1-deficiency epilepsy is a consequence of early brain neurodevelopmental defects, in particular at the level of inhibitory network wiring.
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