Effect of Seizures on the Developing Brain and Cognition

Responsable de l’encadrement : Nadia Soussi-Yanicostas
Tél : 01 40 03 19 31
E-mail: nadia.soussi@inserm.fr

INSERM UMR1141- NeuroDiderot -Université de Paris, Hôpital Robert

Résumé du projet

Epilepsy is the most frequent neurological disorder, affecting approximately 1% of people
worldwide. The disease is characterized by recurrent seizures due to synchronous hyperexcitation of
large populations of brain neurons. Moreover, in severe developmental and epileptic
encephalopathies caused by early brain defects, such as Dravet syndrome, violent and frequent
seizures during the very first years of life frequently cause permanent psychomotor deficits and
recurrent seizures. Numerous antiepileptic drugs have been developed, but they are ineffective in at
least one-third of patients, especially for developmental and epileptic encephalopathies children, a
failure likely related to the neurocentrism of these therapies, which have so far almost completely
overlooked non-neuronal cells, and especially microglia, the resident brain macrophages. It has long
been known that seizures induce MG-mediated brain inflammation and massive secretion of proinflammatory mediators,a complex and highly regulated process that is mainly mediated by microglia,
a population of resident macrophages, which colonize the cerebral parenchyma during early brain
development in vertebrates. However, while neuroinflammation was seen until recently as a mere
consequence of neuron over-excitation, recent data suggest that microglial cell activities play an
important role in the physiopathology of epilepsy. However, and most importantly, whether microglia
activities are beneficial or, on the contrary, harmful for post-seizure brain functioning, is an unresolved
and critical issue that has tremendous implications for the development of novel therapeutic strategies
The goal of this project thesis is to better understand the role of microglial cells in epilepsy. For this,
our team takes advantage of the large set of in vivo approaches allowed by the zebrafish (Danio
rerio). Specifically, we combine genetic techniques (epileptic mutant lines and transient gene knockdown) with imaging (confocal microscopy and calcium imaging), electrophysiological (EEG) and
molecular approaches, to precisely characterize the phenotypic and molecular changes of microglial
cells, which are induced by epileptic seizures, and better understand the consequences of these
changes on subsequent brain functioning and neuron excitation.

Publications les plus significatives dans la période de référence (2017-2021)
1. Brenet A, Hassan-Abdi R, and Soussi-Yanicostas N.
Bixafen, a succinate dehydrogenase inhibitor fungicide, causes microcephaly and motor neuron axon defects during development.
Chemosphere. 2020 Oct 27:128781. doi: 10.1016/j.chemosphere.2020.128781
2. Brenet A, Somkhit J, Hassan-Abdi R, Yanicostas C, Romain C, Bar O, Igert A, Saurat D, Taudon N, Dal-Bo G, Nachon F, Dupuis N, and SoussiYanicostas N.
Organophosphorus diisopropylfluorophosphate (DFP) intoxication in zebrafish larvae causes behavioral defects, neuronal hyperexcitation and
neuronal death
Sci Rep. 2020 Nov 5;10(1):19228. doi: 10.1038/s41598-020-76056-8.
3. Maupu C, Enderlin J, Igert A, Oger M, Auvin S, Hassan-Abdi R, Soussi-Yanicostas N, Brazzolotto X, Nachon F, Dal Bo G, Dupuis
N.Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice.
Neurobiol Dis. 2021 Jan 30;152:105276.
4. Brenet A, Hassan-Abdi R, Somkhit J, Yanicostas C, and Soussi-Yanicostas N
Defective Excitatory/Inhibitory Synaptic Balance and Increased Neuron Apoptosis in a Zebrafish Model of Dravet Syndrome
Cells. 2019 Oct 4;8(10). pii: E1199. doi: 10.3390/cells8101199.
5. Mairesse J, Zinni M, Pansiot J, Hassan-Abdi R, Demene C, Colella M, Charriaut-Marlangue C, Rideau Batista Novais A, Tanter M, Maccari S,
Gressens P, Vaiman D, Baud* O, and N Soussi-Yanicostas*
Co-last authors.
Oxytocin receptor agonist reduces perinatal brain damage by targeting microglia.
Glia. 2019 Feb;67(2):345-359. doi: 10.1002/glia.23546.
6. Van Steenwinckel J, Schang A-L, Krishnan ML, et al. N Soussi-Yanicostas, B Fleiss, P Gressens.
Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain.
Brain. 2019;142(12):3806-3833. doi:10.1093/brain/awz319
7. Alavi Naini SM, Yanicostas C, Hassan-Abdi R, Blondeel S, Bennis M, Weiss RJ, Tor Y, Esko JD, and Soussi-Yanicostas N.
Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy.
Transl Neurodegener. 2018 Mar 16;7:6. doi: 10.1186/s40035-018-0111-2.
8. Naini SMA, Soussi-Yanicostas N.
Heparan sulfate as a therapeutic target in tauopathies: Insights from zebrafish.
Front Cell Dev Biol. 2018;6(DEC). doi:10.3389/fcell.2018.00163
9. Samarut É, Swaminathan A, Riché R, Liao M, Hassan-Abdi R, Renault S, Allard M, Dufour L, Cossette P, Soussi-Yanicostas N, Drapeau P.

Ce projet s’inscrit-il dans la perspective d’une thèse :
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Ecole Doctorale de rattachement : Ecole doctorale BioSPC

Equipe d’Accueil : NeuroDiderot
Intitulé de l’Unité : INSERM UMR1141- NeuroDiderot -Université de Paris, Hôpital Robert
Nom du Responsable de l’Unité : P. Gresse
Nom du Responsable de l’Équipe : Nadia Soussi-Yan