Objectives and projects

Our goal is to deepen our understanding of the pathophysiological mechanisms of focal epilepsies – the most common forms of epilepsy in adults and often refractory to antiepileptic drugs – from a translational perspective, with the aim of identifying new targets for more specific and effective treatments. Our projects are based on ongoing and particularly promising recent research, but also include new developments. They are based on a wide range of multi-scale experimental approaches, ranging from single molecule imaging to electrophysiological studies of network dynamics in vitro in post-operative human brain tissue, as well as in vivo in relevant animal models .

Currently, our main projects focus on:

– The neuronal mechanisms of chloride ion transport: since GABAA receptors are mainly permeable to chloride ions, the currents they carry are directly influenced by transmembrane gradients of chloride in neurons. We study the function and regulation of the chloride/cation co-transporter KCC2, which exerts a major control over these gradients in mature cortical neurons (Chamma et al J Neurosci 2013 ; Heubl et al Nat Comm 2017 ; Otsu et al J Physiol 2020 ; Al Awabdh et al J Neurosci 2021), the functional impact of its down-regulation, as observed in many neurological disorders such as focal epilepsies (Gauvain et al PNAS 2011 ; Chevy et al J Neurosci 2015 ; Goutierre et al Cell Rep 2019; Simmonet et al Neuropsychopharmacology 2023), as well as the therapeutic potential of KCC2 enhancing drugs in pharmacoresistant epilepsy (Donneger et al bioRxiv 2023). Current projects focus on the functional impact of mutations affecting the Slc12a5 gene encoding KCC2 and associated with epilepsy, and the role of KCC2 in early cortical development.

– The cellular architecture of epileptic networks: in focal epilepsies, interictal and ictal activities are usually initiated in restricted areas of the epileptogenic zone. Using resective brain samples from pharmacoresistant epileptic patients as well as animal models, we explore the cellular and molecular identity of epileptogenic networks by implementing i) unbiased approaches coupled with transcriptomic analyses to reveal the identity of cells and circuits recruited during pathological activities and ii) interventional approaches to assess the causal link between the activity of specific neurons and ensembles and the emergence of seizures. These projects involve electrophysiological recordings from human postoperative brain samples in vitro, single cell (patch-seq) as well as spatial transcriptomic analyses, activity-dependent tagging of active neuronal ensembles and opto/chemo-genetic manipulation of neuronal activity.

– The regulation of neuronal excitability by Kv2.1 channels: Kv2.1 are required for membrane repolarization after high frequency firing, thereby regulating firing freqeuncy in neurons. Numerous mutations in the KCNB1 gene encoding Kv2.1 channels have recently been identified in patients with encephalopathic epilepsies. These disorders are characterized by genralized brain dysfunction with epileptic seizures and cognitive impairment. We perform integrated and multi-level exploration (from molecules to neural networks) the mechanisms by which Kv2.1 controls neuronal excitability and how these are affected by mutations.

In 2025, our team will join the Paris Brain Institute.

Experimental approaches

We use a multidisciplinary approach combining:
• in vitro (patch clamp, LFP and MEA) and in vivo (ECoG, silicon probes) electrophysiology
• anterograde tracing and genetic expression/suppression using viral vectors
• opto/chemo-genetics
• activity-dependent neuronal tagging
• optical imaging on live neurons
• super-resolution microscopy (STED/PALM/STORM)
• single molecule tracking using quantum dots, sptPALM et uPAINT probes) electrophysiology
• anterograde tracing and genetic expression/suppression using viral vectors
• optogenetics
• optical imaging on live neurons
• super-resolution microscopy (STED/PALM/STORM)
• single molecule tracking using quantum dots, sptPALM et uPAINT
• postoperative human brain tissue
• biochemistry and proteomics

Our team will be joining the Paris Brain Institute in 2025.

Composition of the team

Team leader : Jean Christophe Poncer (DR Inserm)

• Marianne Renner, Professor Sorbonne Université
• Sophie Longueville, Engineer Inserm

• Carla Pagan, PhD student, Sorbonne Université
• Mélina Scopin, PhD student, Sorbonne Université
• Esther Bliard, PhD student, Sorbonne Université
• Capucine Gendre, PhD student, Sorbonne Université
• Camila Morel Soto, MSc intern, Université Paris-Saclay

Anciens membres de l’équipe

• Marion Russeau (ESPCI, Paris)
• Sabine Lévi (ESPCI, Paris)
• Florian Donneger (Stanford University, USA)
• Sana Al Awabdh (UFR Biomédicale, Univ de Paris)
• Clémence Simonnet (Univ. Geneve, Suisse)
• Etienne Côme (Utopies, Paris)
• Manisha Sinha (Dept of Psychology, Univ Michigan, Ann Arbor, USA)
• Yo Otsu (Kollig Institute for Medical Research, Sydney, Australie)
• Jessica C Pressey (Dept of Cell and Systems Biology, Univ Toronto, Canda)
• Eric J Schwartz (SPPIN, Paris)
• Ferran Gomez-Castro (Barcelone, Espagne)
• Martin Heubl (Laboratoires IPSEN, Paris)
• Quentin Chevy (Cold Spring Harbor Lab., NY, USA)
• Ingrid Chamma (Institut Magendie, Bordeaux)
• Nicolas Le Roux (Ministère des Finances, Paris)
• Micèle Carnaud (retraitée)
• Carolina Cabezas (Madrid, Espagne)
• Grégory Gauvain (Institut de la Vision, Paris)
• Walid Bouthour (Hôpitaux Universitaires de Genève, Suisse)
• Félix Leroy (Columbia University, NY, USA)

Funding and affiliation

Our team has received the “FRM Team” label in 2014, from the Fondation pour la Recherche Médicale (FRM). Our projects are currently supported by Inserm, ERANET-Neuron and Agence Nationale pour la Recherche (ANR). Our team is affiliated to Inserm and Sorbonne University as well DIM C-BRAINS.