Poncer / Lévi

Objectives and projects

Our team explores the properties of cortical synapses and networks, the mechanisms governing their plasticity and their alteration in the pathology. Our work focuses in particular on GABAergic synapses and networks underlying inhibitory neurotransmission in the adult brain.
Our aim is to understand the molecular mechanisms that regulate the organization, the function and the plasticity of GABAergic synapses and networks. We hope to identify therapeutic targets of interest for disorders involving malfunction of GABA neurotransmission, such as epilepsy and Rett syndrome as well as psychiatric conditions such as bipolar disorders.

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), as well the functional impact of its down-regulation, as observed in many neurological and psychiatric disorders (Gauvain et al PNAS 2011 ; Chevy et al J Neurosci 2015 ; Goutierre et al Cell Rep 2019).

– The synaptic anchoring of GABAA receptors: GABAA receptors rapidly diffuse in the neuronal membrane but are captured at inhibitory synapses, in particular through interactions with the scaffolding protein gephyrin. This anchoring determines the number of synaptic receptors and therefore the function of GABAergic synapses. We examine the molecular determinants of GABAA receptor anchoring, its modulation by neuronal activity (Lévi et al Neuron 2008) as well as the impact of human mutations affecting GABAA receptors or gephyrin and associated with neurological and psychiatric disorders (Eugène et al J Neurosci 2013 ; Bouthour et al Cereb Cortex 2012 ; Lévi et al Neurpharmacology 2015). We also explore the short- and long-term consequences of chronic caffeine exposure, in particular during early postnatal development, on GABAergic synapse stabilization.

– 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.

Experimental approaches

We use a multidisciplinary approach combining:
• in vitro (patch clamp, LFP and MEA) and in vivo (ECoG) 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
• biochemistry and proteomics

Composition of the team

Team leaders: Jean Christophe Poncer (DR Inserm) et Sabine Lévi (DR CNRS)

• Marianne Renner, Professor Sorbonne University
• Xavier Marquès, Engineer Sorbonne University
• Marion Russeau, Technician INSERM
• Etienne Côme, graduate student Sorbonne University
• Florian Donegger, graduate student Sorbonne University

• Zaha Merlaud, undergraduate Sorbonne University
• Claire Montmasson, Engineer INSERM
• Anne-Lise Paupiah, undergraduate Sorbonne University
• Youcef Kadri, undergraduate Paris University
• Yoness Kadiri, undergraduate Ecole Centrale de Lyon

Former team members:

• Yo Otsu (Kolling Institute for Medical Research, Sydney, Australia)
• Ferran Gomez-Castro (Barcelona, Spain)
• Martin Heubl (Laboratoires IPSEN, Paris)
• Quentin Chevy (Cold Spring Harbor Laboratory, NY, USA)
• Ingrid Chamma (Institut Magendie, Bordeaux)
• Nicolas Le Roux (Ministère des Finances)
• Michèle Carnaud (retired)
• Carolina Cabezas (Madrid, Spain)
• Grégory Gauvain (Institut de la Vision, Paris)
• Katherine Matho (Cold Spring Harbor Laboratory, NY, USA)
• Walid Bouthour (Hôpitaux Universitaires de Genève)
• Félix Leroy (Columbia Univ., 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 also currently supported by INSERM, Fédération pour la Recherche sur le Cerveau (FRC), Fondation Française pour la Recherche sur l’Epilepsie (FFRE), ERANET-Neuron and Agence Nationale pour la Recherche (ANR). Our team is affiliated to INSERM, UPMC, the BioPsy Laboratory of Excellence and the Ecole des neurosciences de Paris network.

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