Dynamics of neuronal excitability



Since the creation of the team, we explore 6 research lines in parallel:
1) synaptic plasticity (Inglebert et al., PNAS 2020; Ho et al., PNAS 2021; Debanne & Inglebert, Curr Opin Neurobiol 2023),
2) plasticity of intrinsic neuronal excitability in hippocampal (Daoudal et al., PNAS 2002; Campanac & Debanne, J Physiol 2008; Campanac et al., J Neurosci 2008; Cudmore et al., J Neurosci 2010; Campanac et al., Neuron 2013; Gasselin et al., J Physiol 2015; Gasselin et al., Sci Rep 2017; Debanne et al., Curr Opin Neurobiol 2019; Incontro et al., J Neurosci 2021; Sammari et al., PNAS 2022), and neocortical neurons ((Sourdet et al., J Neurosci 2003; Carlier et al., J Physiol 2006),
3) synaptic and intrinsic factors controling neuronal timing ((Sourdet et al., J Neurosci 2003; Boudkkazi et al., Neuron 2007; Cudmore et al., J Neurosci 2010; Boudkkazi et al., J Physiol 2011; Gastrein et al., J Physiol 2011; Caillard PLoS One 2011; Dubruc et al., J Neurophysiol 2013),
4) synaptic and intrinsic properties of extra-ocular (abducens) motoneurones (Russier et al., J Physiol 2002; Russier et al., J Physiol 2003),
5) axonal function (Kopysova & Debanne, J Neurosci 1998; Bialowas et al., EJN 2015; Rama et al., Nat Commun 2015; Rama et al., Sci Rep 2017; Zbili & Debanne, Front Cell Neurosci 2020; Zbili et al., Sci Adv 2020; Fékété et al., PNAS 2021; Zbili et al., PNAS 2021).
6) role of LGI1 protein in the tuning of neuronal excitability (Seagar et al., PNAS 2017; Ramirez-Franco et al., Brain 2022; Extrémet et al., Cells 2022)

We explore 4 main research themes in parallel: 1) plasticity of intrinsic neuronal excitability, 2) synaptic plasticity, 3) axon function and 4) LGI1 and neuronal excitability.

Intrinsic plasticity
Long-lasting plasticity of synaptic transmission is classically thought to be the cellular substrate for information storage in the brain. Recent data indicate however that it is not the whole story and persistent changes in the intrinsic neuronal excitability have been shown to occur in parallel to the induction of long-term synaptic modifications. A large part of our research activity is devoted to the characterization of interactions existing between synaptic and intrinsic plasticity. We have established that learning rules defined for synaptic transmission (BCM, STDP) are also valid for plasticity of dendritic integration in CA1 pyramidal neurons (Daoudal et al., PNAS 2002; Campanac & Debanne, J Physiol 2008). We show that h-channel activity is reduced in the dendrites following induction of potentiation of dendritic integration (Campanac et al., J Neurosci 2008). We demonstrate for the first time that GABAergic interneurons also express plasticity of intrinsic neuronal excitability (Campanac et al. Neuron 2013; Incontro et al., J Neurosci 2021; Sammari et al., PNAS 2022). We have identified the role of HCN channels in the homeostatic regulation of intrinsic excitability in CA1 neurons (Gasselin, et al., J Physiol 2015; Gasselin et al., Sci Rep 2017). We are now exploring i) the mechanisms of activity-dependent regulation of Kv1 channels (ANR Blanc Neuroscience 2011 Reprek), ii) the mechanisms underlying intrinsic plasticity induced in parallel with synaptic LTD and iii) the role of intrinsic plasticity in amblyopia (FRM Physiopathology of the visual system 2013; ANR Plastinex 2021).

Neuronal timing
We explore the factors determining neuronal synchronization at 2 strategic points of the neuron: the synapse and the axon initial segment. We have established that the synaptic delay is not constant but rather depends on release probability (Boudkkazi et al., Neuron 2007) and presynaptic spike waveform (Boudkkazi et al., J Physiol 2011). Thus, synaptic delay is modified during several forms of short- and long-term synaptic plasticity.
We have also demonstrated the role of voltage trajectories preceding the spike in temporal precision of spike firing (Sourdet et al., J Neurosci 2003; Cudmore et al., J Neurosci 2010; Gastrein et al., J Physiol 2011). These voltage trajectories are finely tuned by many voltage-gated ionic currents that specifically affect the first action potential (D-type current meidate by Kv1 channels or H-type cationic current) or secondary action potentials (mAHP current meidated by SK channels). We also explore the role of inhibitory synaptic activity in the precision of neuronal discharge (Caillard, PLoS One 2011; Dubruc et al., J Neurophysiol 2013).

Finally, our work also examines how voltage-gated ion channels in the axon determine information processing in hippocampal and neocortical circuits (Debanne et al. Nature 1997; Kopysova & Debanne, J Neurosci 1998; Debanne, Nat Rev Neurosci 2004; Debanne et al., Physiol Rev 2011). Our project is aimed at determining the axonal mechanisms of analog-digital modification of synaptic strength (Debanne et al., Nat Rev Neurosci 2013; Bialowas et al. EJN 2015; Rama et al., Nat Commun 2015; Zbili et al., Sci Adv 2020) and the role of axonal Kv1 channels on intrinsic excitability measured in the cell body (Rama et al., Sci Rep 2017).

LGI1 and epilepsy
We have shown that the lack of LGI1 protein increased neuronal excitability and transmitter release through a reduction of the DTX-sensitive current, thus accounting for the epilepsy observed in patient lacking LGI1 (Seagar et al., PNAS 2017). We have shown that antibodies against the LRR region but not against the EPTP region increased excitability in CA3 neurons (Extrémet et al., Cells 2022).

Internal: Oussama El Far (ANR Blanc Biologie Cellulaire 2011 MOMENT; FRM 2013).
Local: Service de biochimie et biologie moléculaire CHU Nord (Pr J Gabert; FRM 2013), Service d'ophtalmologie (Pr D Denis; FRM 2013)
National: JC Poncer (INSERM Paris; ANR NMP 2008 EPISOM), Agnès Baude (INSERM, Marseille), Stéphanie Baulac (INSERM, Paris; ANR Blanc Neurosciences 2011, REPREK), Romain Brette (Institut de la Vision, Paris; ANR Axode 2014-2017) & Boris Barbour (IBENS Paris; NSF-ANR Syncity 2014)
International:  JJ Garrido (CSIC, Madrid) & Nicolas Brunel (Chicago, USA; NSF-ANR Syncity 2014)

Our group uses all the electrophysiological methods in vitro (acute slices of brain tissue and organotypic slice cultures of hippocampus). We have 6 patch-clamp rigs mostly equipped with fluorescent cameras and multiple micromanipulators to allow simultaneous recording from the same neuron (soma/dendrite (Campanac et al., J Neurosci 2008), or soma/axon (Boudkkazi et al., Neuron 2007; Boudkkazi et al., 2011; Rama et al., 2015) or synaptic recording from pairs of connected neurons (Boudkkazi et al., Neuron 2007; Debanne et al., Nat Prot 2008; Boudkkazi et al., J Physiol 2011; Gastrein et al., J Physiol 2011; Rama et al., Nat Commun 2015; Zbili et al., Sci Adv 2020). One patch clamp set-up is equipped with a confocal microscope (LSM710 Zeiss) which allows us to combine high resolution imaging of calcium, sodium and voltage with electrophysiological recording on acute slices or cultures (Bialowas et al., EJN 2015; Rama, Front Cell Neurosci 2015; Rama et al., Nat Commun 2015; Rama et al., Sci Rep 2017; Zbili et al., Sci Adv 2020; Inglebert et al., PNAS 2020; Fékété et al., PNAS 2021). We also use modeling and hybrid techniques (dynamic-clamp (Sourdet et al. J Neurosci 2003; Cudmore et al. J Neurosci 2010; Rama et al., 2015; Zbili et al., 2020; Fékété et al., 2021) and hybrid networks (Cudmore et al., J Neurosci 2010)) to identify the functional consequences of intrinsic plasticity.

Our group is supported by INSERM, CNRS, Ministère de la Recherche, Fondation Recherche Médicale, European Community, Agence Nationale de la Recherche, Ecole Normale Supérieure, Institut Méditerranéen de Recherche Avancée (IMéRA) and Région PACA

Current grants:
FRM Equipe 2019-2023
Région SUD "DESOMLIBEX" 2021-2024
A*Midex, Equipment 2023-2025
FRC, Molecular mechanisms of visual thalamus plasticity, 2023-2024
A*Midex, Release of somatostatine by interneurons 2024-2026
ANR, "SYNCHROSYN" Régulation de la transmission synaptique dépendante de la synchronie, 2023-2027


ALCARAZ Gisèle, BIALOWAS Andrzej , BOUDKKAZI Sami, CAILLARD Olivier , CAMPANAC Emilie, CARLIER Edmond , COQ Olivier , CUDMORE Robert H, DAOUDAL Gaël, DEGLISE Patrice, DUBRUC Franck , DUMENIEU Maël, EXTREMET Johanna, FEKETE Aurélie, GASSELIN Célia , GASTREIN Philippe, GIRAUD Pierre , GOAILLARD Jean-Marc , INGLEBERT Yanis, MARRA Vincenzo , PIERALI Hélia, RAMA Sylvain , SAMMARI Malika, SOURDET Valérie, WAKADE Anushka, ZANIN Emilie, ZBILI Mickaël.


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