CE17 - Recherche translationnelle en santé

Chloride Deregulation in Epileptic Focal Cortical Dysplasia – DYSCLO

Submission summary

Focal cortical dysplasia (FCD) are epileptogenic malformations of cortical development leading to drug resistant epilepsy in children. Surgical treatment is the gold standard to treat these patients and offers the unprecedented opportunity to better understand the mechanisms of epilepsy exvivo. I have trained as a neurosurgeon and have recently been appointed to lead the epilepsy surgery unit at Necker Hospital following a postdoctoral fellowship at Harvard University where I studied physiological mechanisms of epileptic activity. The dual objectives of my work combining fundamental and clinical research are to optimize the accuracy of neurosurgery in FCD while defining molecular and physiological mechanisms leading to this disorder. Recently, somatic mutations in the PI3/AKT/mTOR pathways have been identified in FCD Type II. Very recently we showed that GABAergic dysfunction secondary to chloride co-transporters expression is abnormal in FCD. However, the pathways linking the molecular and genetic alterations to functional abnormalities and altered physiological excitability are certainly missing and provide the hypothesis of this research project. The aim of my proposal is to advance our understanding of epileptogenic mechanisms in FCD II through a precise mapping of the generators of epileptic activities in vitro, thus allowing histological and molecular comparison of epileptic to non-epileptic areas, at the network and cellular levels. I postulate that defects in the PI3K/AKT/mTOR pathway due to genetic mutations can directly deregulate the cation chloride cotransporters expressions and activity, leading to a shift in ECl- and depolarizing GABAergic transmission. I will address this hypothesis in the following 4 work packages. In WP1 we will map the epileptic activity of the FCD tissue in vitro. Here we will use multi-electrode array (MEA) recordings to provide a high-resolution cartography of epileptic vs. non-epileptic areas of the patient cortical slices based on both spontaneous and induced seizure-like activity. Functional studies will be immediately followed by slice preparation for histology or laser microdissection to separate epileptic and silent areas for correlative analysis in the following 2 WPs. In WP2 we will dissect Cl- regulatory pathways. This WP aims at unraveling the posttranslational regulation and functional association between mTOR pathway mutation and Cl- cotransporters with protein expression studies comparing epileptic areas to control cortex through targeted and unbiased approaches. In WP3 we will focus on the segregation of the cell types and their specific signatures. Micro-dissected epileptic and non-epileptic areas of the same FCD case will be used for single cell transcriptomic analysis which have the potential to define molecular networks dysregulated in response to the PI3K/AKT/mTOR hyperactivation in FCD II and to identify new druggable targets that can be tested in our slice preparation. In WP4 we will analyze the effect of pharmacological modulation on neural activity. Pharmacological modulation of Cl- cotransporters, WNK-SPAK/OSR1 and PI3K/AKT/MTOR pathways during MEA recordings will determine their effect on the epileptic like activity directly on the patient’s tissue. Post treatment immunohistology and proteomics will allow to dissect the phosphorylation cascades. Overall, this correlative physiology-histology-proteomics approach will allow us to rapidly test candidate therapeutic compounds arising from identified dysregulated pathways in WP2-3. Altogether, translation of this research project onto clinical practice paves the way to personalized medicine in epilepsy surgery with prediction of the seizure recurrence risk, and identification of patient specific mutations and treatment on the margins of resection of the epileptic dysplastic cortex. Therefore, this project should have a direct impact to a better understanding and cure of FCD and related epileptic disorders.

Project coordination


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.



Help of the ANR 377,114 euros
Beginning and duration of the scientific project: December 2020 - 48 Months

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