Neuronal coding and plasticity in epilepsy

Neuronal coding and plasticity in epilepsy

The team aims at studying the synaptopathy, as well as the role of interneurons and adhesion molecules in the neuronal hypexcitability leading 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 Temporal Lobe 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 Interests. The team tackles three major topics:
1)The role of kainate receptors in seizure activities
2)The role of principal cells and interneuronsin the alterations of coding properties and the generation of seizures in epileptic conditions
3)The role of cell adhesion molecules involved in neuropathies and seizures Team’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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Last Publications:

Ouedraogo DW, Lenck-Santini PP, Marti G, Robbe D, Crépel V, Epsztein J. Abnormal UP/DOWN Membrane Potential Dynamics Coupled with the Neocortical Slow Oscillation in Dentate Granule Cells during the Latent Phase of Temporal Lobe Epilepsy. eNeuro. 2016 May 31;3(3).

Artinian J, Peret A, Mircheva Y, Marti G, Crépel V. Impaired neuronal operation through aberrant intrinsic plasticity in epilepsy. Ann Neurol. 2015 Jan 13.

Crépel V, Mulle C. Physiopathology of kainate receptors in epilepsy. Curr Opin Pharmacol. 2015 Feb;20:83-8.

Peret A, Christie LA, Ouedraogo DW, Gorlewicz A, Epsztein J, Mulle C, Crépel V. Contribution of aberrant GluK2-containing kainate receptors to chronic seizures in temporal lobe epilepsy. Cell Rep. 2014 Jul 24;8(2):347-54.

INSERM Transfert filed patents:

– Method and pharmaceutical composition for use in the treatment of epilepsy (V. Crépel, C. Mulle, A. Peret; WO/2015/036618)
– Methods and pharmaceutical composition for the treatment of post-traumatic epilepsies (C. Rivera, V. Crépel, C. Pellegrino, N. Kourdougli; EP15306384)

Scientific Interests

We investigate neuronal computation and plasticity in normal and pathological conditions. Our studies are conducted at multiscale levels i.e. from the individual spine to the microcircuit.

Disease conditions: Temporal Lobe Epilepsy and Traumatic Brain Injury.

Key words: hippocampus, cerebellum, synapse, intrinsic property, plasticity, synaptopathy, calcium

Technical skills: (i) in vitro and in vivo electrophysiological recordings; (ii) calcium imaging; (iii) morphometric analysis; (iv) optogenetic; (v) spatial navigation in virtual reality environments.

Kainate receptors in the physiopathology of temporal lobe epilepsy

Temporal Lobe Epilepsy (TLE) is the most common form of partial epilepsy in adults is often refractory to pharmacological medication. Moreover, patients with TLE also often suffer from comorbid disorders including cognitive impairments. Therefore, it is crucial to better understand the physiopathology of TLE in order to propose new anti-epileptic strategies and shed light on putative alterations of neuronal computation.

We show that recurrent mossy fibers synapses operate via kainate receptors not present in naïve conditions (Epsztein et al. 2005). These synapses profoundly affect synaptic transmission by generating synaptic events with slow kinetics. Because of this feature, we show that KAR-operated synapses impose an aberrant synaptic temporal integration, a wrong tempo of firing and trigger a long-lasting intrinsic plasticity in epileptic dentate granule cells (Epsztein, Sola et al. 2010; Artinian et al. 2011; Artinian et al 2015). We propose that these changes of neuronal computation may contribute to the impairment of dentate gyrus functions such as gate function and pattern separation in TLE.

In collaboration with C. Mulle (IINS, Bordeaux), we recently demonstrate that GluK2/GluK5 kainate receptors ectopically expressed in dentate granule cells play a major role in recurrent seizures in TLE (Peret, Christie et al. 2014;Crepel and Mulle 2014). This should revitalize the development of new pharmacological agents and strategies directly targeting these KARs as novel antiepileptic drugs: INSERM Transfert filed patent: WO/2015/036618.

Collaborators

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

EXTERNAL
Dr. C. Mulle (Institut des Neurosciences, Bordeaux)
Pr. F. Bartolomei (Hopital Timone, Marseille)
Pr. D. Scavarda (Hopital Timone, Marseille)
Dr. Jean-François Perrier (Copenhagen, Danemark)
Dr. M. Simonneau (Centre de Psychiatrie & Neurosciences, Paris)

Former members

– Jérôme Epsztein (CR1, INSERM)
– Thomas Scalfati (Master Student)
– Saara Valpurla (Master Student, Erasmus)
– Julien Artinian (Post-doc.)
– Geoffrey Marti (Master Student)
– Louisa Christie (Post-Doc.)
– David Ouedraogo (PhD student)
– Yanina Mircheva (Master Student)
– Karen Arnaud (Master Student)

Funding

2013 – 2017 : ANR « Blanc » (TRAUMEP, C. RIVERA & V. CREPEL)
2013-2014: LFCE (A. PERET, V. CREPEL)
2011 : région PACA : Appel à Projets Ouverts (projet APO, V. CREPEL)
2011-2012: LFCE (J. ARTINIAN, V. CREPEL)
2010 – 2014: ANR « Blanc » (KAREP, C. MULLE & V. CREPEL)
2010 FRC / Rotary (A. REPRESA & V. CREPEL)
2009 – 2012: ANR « Blanc » (Epileptic Code, V. CREPEL)
2006 – 2009: ANR MNP (CDDRat, A. REPRESA & V. CREPEL)

Join our team !

Our team has open positions for master students, PhD students and post-docs. Please send your application by email to Valérie Crépel

L'équipe

Valérie CREPEL Research Director

Catherine FAIVRE-SARRAILH Researcher Emeritus

Edouard PEARLSTEIN Researcher

Céline BOILEAU Research engineer

Lucas GOIRAND-LOPEZ Postdoc

Alexandre VIGIER Post-doc

Léo GOLDSTEIN PhD Student

Nicolas PARTOUCHE Engineer - uniQure

Nos publications

Abnormal UP/DOWN Membrane Potential Dynamics Coupled with the Neocortical Slow Oscillation in Dentate Granule Cells during the Latent Phase of Temporal Lobe Epilepsy.

Ouedraogo DW, Lenck-Santini PP, Marti G, Robbe D, Crépel V, Epsztein J

eNeuro - Jun May 2016

Impaired neuronal operation through aberrant intrinsic plasticity in epilepsy.

Artinian J, Peret A, Mircheva Y, Marti G, Crépel V

Annals of neurology - Jan 2015

Physiopathology of kainate receptors in epilepsy.

Crépel V, Mulle C

Current opinion in pharmacology - Dec 2014

Contribution of aberrant GluK2-containing kainate receptors to chronic seizures in temporal lobe epilepsy.

Peret A, Christie LA, Ouedraogo DW, Gorlewicz A, Epsztein J, Mulle C, Crépel V

Cell reports - Jul 2014

Activity-dependent gating of calcium spikes by A-type K+ channels controls climbing fiber signaling in Purkinje cell dendrites.

Otsu Y, Marcaggi P, Feltz A, Isope P, Kollo M, Nusser Z, Mathieu B, Kano M, Tsujita M, Sakimura K, Dieudonné S

Neuron - Oct 2014

The information content of physiological and epileptic brain activity.

Trevelyan AJ, Bruns W, Mann EO, Crepel V, Scanziani M

The Journal of physiology - Feb 2013

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

Inhibitory actions of the gamma-aminobutyric acid in pediatric Sturge-Weber syndrome.

Tyzio R, Khalilov I, Represa A, Crepel V, Zilberter Y, Rheims S, Aniksztejn L, Cossart R, Nardou R, Mukhtarov M, Minlebaev M, Epsztein J, Milh M, Becq H, Jorquera I, Bulteau C, Fohlen M, Oliver V, Dulac O, Dorfmüller G, Delalande O, Ben-Ari Y, Khazipov R

Annals of neurology - Aug 2009

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

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

Seizures beget seizures in temporal lobe epilepsies: the boomerang effects of newly formed aberrant kainatergic synapses.

Ben-Ari Y, Crepel V, Represa A

Epilepsy currents / American Epilepsy Society -

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

A parturition-associated nonsynaptic coherent activity pattern in the developing hippocampus.

Crépel V, Aronov D, Jorquera I, Represa A, Ben-Ari Y, Cossart R

Neuron - Apr 2007

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

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

The ammonium-induced increase in rat brain lactate concentration is rapid and reversible and is compatible with trafficking and signaling roles for ammonium.

Provent P, Kickler N, Barbier EL, Bergerot A, Farion R, Goury S, Marcaggi P, Segebarth C, Coles JA

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism - Nov 2007

The role of glial glutamate transporters in maintaining the independent operation of juvenile mouse cerebellar parallel fibre synapses.

Marcaggi P, Billups D, Attwell D

The Journal of physiology - Oct 2003

Functional Ca2+ and Na+ channels on mouse Schwann cells cultured in serum-free medium: regulation by a diffusible factor from neurons and by cAMP.

Beaudu-Lange C, Despeyroux S, Marcaggi P, Coles JA, Amédée T

The European journal of neuroscience - May 1998

Effects of photoreceptor metabolism on interstitial and glial cell pH in bee retina: evidence of a role for NH4+.

Coles JA, Marcaggi P, Véga C, Cotillon N

The Journal of physiology - Sep 1996

Neuronal coding and plasticity in epilepsy