Team 3 : Plasticity in cortical networks and epilepsy (Poncer / Lévi)

Team leaders : Jean-Christophe Poncer (DR2 Inserm) and Sabine Lévi (DR2 CNRS)

Team 3: Plasticity in cortical networks and epilepsy (Poncer / Lévi) Team website

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), 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).

- Synaptic recruitment of GABAergic interneurons: GABAergic interneurons are recruited by the activity of cortical networks through activation of glutamatergic, excitatory synapses impinging from neighboring and distant principal neurons. These synapses therefore critically influence the ability of GABAergic interneurons to detect and adapt their activity to network activity, in particular during both normal and pathological rhythmic activities. We explore the function and plasticity rules of these synapses in identified interneurons populations (Le Roux et al J Physiol 2013) and their alteration in animal models of temporal lobe epilepsy.

- 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). We also explore the short- and long-term consequences of chronic caffeine exposure, in particular during early postnatal development, on GABAergic synapse stabilization.

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 (DR2 Inserm) and Sabine Lévi (DR2 CNRS)
• Marianne Renner, PU UPMC
• Eric Schwartz, MC UPMC
• Marion Russeau, TR INSERM
• Sana Al Awabdh, postdoctoral fellow INSERM
• Jessica Pressey, postdoctoral fellow INSERM
• Yo Otsu, postdoctoral fellow UPMC
• Marie Goutierre, graduate student UPMC
• Ferran Gomez-Castro, graduate student UPMC
• Clémence Simonnet, graduate student UPMC
• Yousra Kouidri, undergraduate, ENS Cachan

Former team members:
• Emmanuel Eugène (IE1 INSERM)
• Martin Heubl (Laboratoires Servier, 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, Espagne)
• 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, the Human Frontier Science Program (HFSP), Bio-Psy LabEx, Fédération pour la Recherche sur le Cerveau (FRC), Fondation Française pour la Recherche sur l'Epilepsie (FFRE), Association Française du Syndrome de Rett (AFSR) 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.