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Codage neuronal et plasticité en condition physiologique et épileptique

Codage neuronal et plasticité en condition physiologique et épileptique

The team aims at studying the synaptopathy, as well as the role of interneurons and adhesion molecules in the neuronal hypexcitabilityleading to the generation of seizures in epileptic conditions. Our studies are conducted at several scales: from the subcellular compartment to the neural microcircuit. The research group has a long history in the study of the physiopathology of TemporalLobe Epilepsy (TLE), which is one of the most common forms of partial epilepsy in adults. In the epileptic hippocampus, dentate granule cells (DGCs) form new recurrent synapses. The team discovered that these synapses are not only aberrant in their localization, but they also are operating via a subtype of glutamatergic receptors not present in naïve conditions, the kainate receptors (KAR, Epsztein et al., 2005). For the past ten years, our studies tackle the impact of these ectopic KARs in neuronal coding and seizure generation in DGCs from animal models of TLE. We showed that ectopic KARs, in addition to a reorganisation of the network, play a central role in TLE by deeply altering the neuronal coding properties, leading to the generation of pathological activities including seizures (Epsztein et al., 2010; Artinian et al., 2011, 2015; Peret et al., 2014). Furthermore, we demonstrated that the expression of GluK2/GluK5 subunits in these ectopic kainate receptors is instrumental for the generation of seizures (Peret, Christie et al., 2014; Crepel & Mulle, 2014). Based on these data, the team published a patent (INSERM Transfer, WO2015036618-A1/N° 10,016,424), and is currently involved in the maturation and the development of new antiepileptic approaches targeting these ectopic kainate receptors. In this context, the team is a member of the FHU EpiNext.In parallel, the research group is focusing on the role of some cell adhesion molecules (CAMs) associated with Kv1 potassium channels in neuropathies characterized by the generation of seizures. More specifically, we study the involvement of the CAMs Caspr2 (CNTNAP2) and LGI1 in neurological diseases of autoimmune or genetic origin leading to epilepsy (Canali et al., 2018; Pinatel et al., 2015; Hivert et al., 2019). We decipher the targeting and the assembly of the Kv1 complex, particularly at the axon initial segment and nodes of Ranvier, in physiological and pathological conditions (Pinatel et al., 2017; Brivio et al., 2017; Hivert et al., 2016). The FHU DHUNE approved this research program.Scientific InterestsThe team tacklesthreemajor topics:1)The role of kainate receptors in seizure activities2)The role of principal cells and interneuronsin the alterations of coding properties and the generation of seizures in epileptic conditions3)The role of cell adhesion molecules involved in neuropathies and seizuresTeam’s skills:In vitro and in vivoelectrophysiology (local field potential, patch-clamp), calcium imaging, cell biology, cell cultures, behaviorand virtual reality, rodent models.

 

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Offre pour un poste d’ingénieur: poste d’ingénieur à pourvoir dans l’équipe dirigée par Valérie Crépel

L’équipe s’intéresse aux altérations morpho-fonctionnelles liées à l’épilepsie chronique dans l’hippocampe. Le projet vise à analyser le rôle de réseaux neuronaux aberrants dans la physiopathologie de l’épilepsie du lobe temporal. Pour réaliser ce projet, l’équipe doit recruter un ingénieur. Ce projet est soutenu par l’Agence Nationale de la Recherche. Le salaire suivra les directives de l’ANR et de l’INSERM.

Au sein de l’équipe et en collaboration avec ses chercheurs, l’ingénieur participera :
- à la préparation des modèles de souris épileptiques
- aux injections stéréotaxiques intra-cérébrales chez des souris
- aux enregistrements EEG et LFP
- à l’analyses cytologiques des cerveaux de souris
- à des analyses de biologie moléculaire et de biologie cellulaire
- au maintien des lignées de souris
- au génotypage des animaux transgéniques
- à l’optimisation des protocoles, le suivi et la transmission des résultats

Les candidats doivent envoyer leur CV et une lettre de motivation décrivant leurs intérêts par courriel à Valérie CREPEL : valerie.crepel@inserm.fr
Plus d’infos sur http://www.inmed.fr

 

Centres d’intérêts scientifiques

The team tackles 3 major questions:

1) The role of kainate receptors in seizure activities
2) The role of interneurons and the alterations of coding properties in normal and epileptic conditions
3) The role of adhesion molecules involved in neuropathies and seizures

Team’s skills:
Electrophysiology (local field potential, patch-clamp), calcium imaging, immuno-histochemistry, morphometry, cell biology, cell cultures, virtual reality, genetic animal models.

 

 

 

Synaptopathy, interneurons, adhesion molecules and epilepsy

The team’s objectives are to study the synaptopathy, the role of interneurons and adhesion molecules leading to seizures and hypexcitability. Our studies are conducted at several scales: from the subcellular compartment to the neural microcircuit.

The team has a long history in the study of the physiopathology of Temporal Lobe Epilepsy (TLE), which is one of the most common forms of partial epilepsy in adults. The team has discovered that newly formed synapses between dentate granule cells (DGCs) are not only aberrant in their localization but also in their mode of operation as they operate via a subtype of glutamatergic receptor, the kainate receptor (KAR) not present in naïve conditions (Epsztein et al., 2005). Our studies tackle the impact of ectopic KARs in neuronal coding operation and seizure activity in DGCs in animal models of TLE. For the past ten years, we have obtained several fundamental data demonstrating that network reorganisation and ectopic kainate receptor play a central role in TLE notably by deeply altering the neuronal coding properties leading to different forms of pathological activities including seizures (Epsztein et al., 2010; Artinian et al., 2011, 2015; Peret et al., 2014). We have demonstrated that kainate GluK2/GluK5 receptors expressed ectopically in granular cells of the toothed gyrus play a major role in recurrent TLE seizures (Peret, Christie et al., 2014; Crepel & Mulle, 2014). Based on these data we have published a patent (INSERM Transfer PCT/EP2014/069709 / WO2015036618-A1/N° 10,016,424). The team is now involved in the maturation and development of new antiepileptic approaches targeting these kainate receptors. In this context, the team is a member of the FHU EpiNext.

Our studies also focus on the role of adhesion molecules associated with Kv1 potassium channels and involved in neuropathies with hyperexcitability. In particular, Caspr2 (CNTNAP2) and LGI1 are associated with neurological diseases of autoimmune or genetic origin that generate epilepsy (Canali et al., 2018; Pinatel et al., 2015). We are studying the addressing and molecular architecture of the Kv1 complex, particularly at the initial segment of the axon and Ranvier nodes (Pinatel et al., 2017; Brivio et al., 2017; Hivert et al., 2016). This research programme is approved by the FHU DHUNE

 

Collaborations

INMED

Dr. C Rivera
Dr. R. Khazipov
Dr. R. Cossart
Dr. J. Epsztein
Dr. PP Lenck-Santini
Dr. I. Bureau
Dr. Represa

EXTERNAL

Dr. C. Mulle (IINS, Bordeaux)

Pr. F. Bartolomei (Timone Hospital, Marseille)

Pr. D. Scavarda (Timone Hospital, Marseille)

Dr. D. Grimm (University of Heidelberg, Germany)

Dr. Bernard Pirotte (University of Liege, Belgium)

Dr. Domna Karagogeos (University of Crete, Greece)

Rejoignez notre équipe !

Nous sommes disposés à accueillir des étudiants en Master, des étudiants souhaitant réaliser une thèse, et des postdocs. Pour plus d’information, nous contacter par e-mail : valerie.crepel@inserm.fr ; catherine.faivre-sarrailh@inserm.fr

Nos publications

An epilepsy-related ARX polyalanine expansion modifies glutamatergic neurons excitability and morphology without affecting GABAergic neurons development.

Beguin S, Crépel V, Aniksztejn L, Becq H, Pelosi B, Pallesi-Pocachard E, Bouamrane L, Pasqualetti M, Kitamura K, Cardoso C, Represa A

Cerebral cortex (New York, N.Y. : 1991) - Jun 2013

Synaptic kainate receptors in interplay with INaP shift the sparse firing of dentate granule cells to a sustained rhythmic mode in temporal lobe epilepsy.

Artinian J, Peret A, Marti G, Epsztein J, Crépel V

The Journal of neuroscience : the official journal of the Society for Neuroscience - Jul 2011

A selective interplay between aberrant EPSPKA and INaP reduces spike timing precision in dentate granule cells of epileptic rats.

Epsztein J, Sola E, Represa A, Ben-Ari Y, Crépel V

Cerebral cortex (New York, N.Y. : 1991) - Apr 2010

Recurrent mossy fibers establish aberrant kainate receptor-operated synapses on granule cells from epileptic rats.

Epsztein J, Represa A, Jorquera I, Ben-Ari Y, Crépel V

The Journal of neuroscience : the official journal of the Society for Neuroscience - Sep 2005

Quantal release of glutamate generates pure kainate and mixed AMPA/kainate EPSCs in hippocampal neurons.

Cossart R, Epsztein J, Tyzio R, Becq H, Hirsch J, Ben-Ari Y, Crépel V

Neuron - Jul 2002

Abnormal network activity in a targeted genetic model of human double cortex.

Ackman JB, Aniksztejn L, Crépel V, Becq H, Pellegrino C, Cardoso C, Ben-Ari Y, Represa A

The Journal of neuroscience : the official journal of the Society for Neuroscience - Jan 2009

Late-onset epileptogenesis and seizure genesis: lessons from models of cerebral ischemia.

Epsztein J, Ben-Ari Y, Represa A, Crépel V

The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry - Feb 2008

Synaptic kainate receptors tune oriens-lacunosum moleculare interneurons to operate at theta frequency.

Goldin M, Epsztein J, Jorquera I, Represa A, Ben-Ari Y, Crépel V, Cossart R

The Journal of neuroscience : the official journal of the Society for Neuroscience - Sep 2007

Ongoing epileptiform activity in the post-ischemic hippocampus is associated with a permanent shift of the excitatory-inhibitory synaptic balance in CA3 pyramidal neurons.

Epsztein J, Milh M, Bihi RI, Jorquera I, Ben-Ari Y, Represa A, Crépel V

The Journal of neuroscience : the official journal of the Society for Neuroscience - Jun 2006

Ischemia induces short- and long-term remodeling of synaptic activity in the hippocampus.

Crepel V, Epsztein J, Ben-Ari Y

Journal of cellular and molecular medicine -
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