γ-Aminobutyric acid receptor alpha 1 subunit loss of function causes genetic generalized epilepsy by impairing inhibitory network neurodevelopment

Autor: Eric Samarut, Patrick Cossette, Liselotte Dufour, Marc Allard, Nadia Soussi-Yanicostas, Solène Renault, Rahma Hassan-Abdi, Pierre Drapeau, Amrutha Swaminathan, Meijiang Liao, Raphaëlle Riché
Přispěvatelé: Department of Neurosciences [Montréal, QC, Canada], Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Molecular Biology and Genetics Unit [Bangalore, India] (Transcription and Disease Laboratory), Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)-Indian Institute of Science, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier de l'Université de Montréal (CHUM), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Centre de recherche du Chum [Montréal] (CRCHUM)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Embryo
Nonmammalian
Light
[SDV]Life Sciences [q-bio]
Green Fluorescent Proteins
Gene Expression
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Inhibitory postsynaptic potential
Epileptogenesis
Clonazepam
Animals
Genetically Modified
Gabra1 loss of function
03 medical and health sciences
Epilepsy
0302 clinical medicine
medicine
Anti-epileptic drugs
Animals
MESH: Epilepsy
Gabra1 loss of function
Zebrafish
High‐throughput antiepileptic drug screening
Anti-epileptic drugs
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Generalized epilepsy
Zebrafish
Loss function
Neurons
biology
Glutamate Decarboxylase
Mortality
Premature
Brain
Gene Expression Regulation
Developmental
medicine.disease
biology.organism_classification
Receptors
GABA-A
High‐throughput antiepileptic drug screening
Disease Models
Animal
030104 developmental biology
Neurology
Neurodevelopmental Disorders
Larva
Mutation
GABAergic
Axon guidance
Anticonvulsants
Epilepsy
Generalized
Neurology (clinical)
Transcriptome
Neuroscience
030217 neurology & neurosurgery
Zdroj: Epilepsia
Epilepsia, Wiley, 2018, 59 (11), pp.2061-2074. ⟨10.1111/epi.14576⟩
ISSN: 0013-9580
DOI: 10.1111/epi.14576⟩
Popis: International audience; Objective: In humans, mutations of the γ-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: We generated a gabra1 −/− zebrafish mutant line displaying highly pen-etrant epileptic seizures. We sought to identify the underlying molecular mechanisms through unbiased whole transcriptomic assay of gabra1 −/− larval brains. Results: 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.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Databáze: OpenAIRE
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