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Cortical development

Research interests

Our team investigates the pathophysiological mechanisms of Malformations of Cortical Development (MCDs). MCDs correspond to either macroscopic (e.g. subcortical band heterotopia) or microscopic abnormalities of the cerebral cortex that arise as a consequence of an interruption to the normal steps of formation of the cortical network. Indeed, normal cortical development requires a very precise and orchestrated mobilisation of various neuron subtypes arising from different regions of the brain, and born at various times, in order to achieve specific laminar positioning and connections with other cells. Until the availability of magnetic resonance imaging, MCDs were thought to be extremely rare disorders. It is now recognized that MCDs are a significant cause of epilepsy (20-40% of drug-resistant childhood epilepsies) and intellectual disability (ID), with most patients presenting in childhood. MCDs may be a result of genetic mutations and/or environmental causes such as in utero infection or ischemia. Mutations of many genes linked to several pathways known to regulate neuronal migration and maturation have been recently described in MCD patients, but the physiopathological mechanisms are poorly understood. Our goal is not only to increase our knowledge on genetically determined MCDs, but also to develop more effective therapeutic strategies for treating seizures and other MCDs based on the comprehension of the pathophysiological mechanisms. For this purpose, we conduct integrated multidisciplinary studies involving morphologists, molecular biologists and electrophysiologists. We have also established national and international collaborations with clinicians and geneticists (through the European consortium “DESIRE”, the EPINEXT”–DHU Aix-Marseille University network and the “DECIPHER”-EraNet Neuron funded project) providing us with a transversal appreciation of our researches.

Specific projects

  • aMolecular mechanisms that underlie functional cortical network development in health and disease.
  • bNeuronal basis of epileptic seizure generation and new therapies.
  • cDevelopmental epilepsies and encephalopathies of genetic and viral origins

Molecular mechanisms that underlie functional cortical network development in health and disease.

Our aim is to decipher the mechanisms that control cortical network development through investigation of genetic mutations associated with MCDs. More precisely, we propose to investigate if and how mutations in MCD genes are involved in the morpho-functional changes underlying the development of cortical connections and networks by answering the following questions: i) what are the roles of MCD genes in neuronal migration?; ii) are these genes involved in axon outgrowth, dendritogenesis or synaptogenesis ?; iii) what are the consequences of mutations in MCD genes on morphology and functional maturation of cortical neurons ?

Acute neocortical slice containing RFP-expressing neocortical neurons (red), mounted on the top of a microelectrode array chip (microphotograph: L Petit

Neuronal basis of epileptic seizure generation and new therapies.

Our group has accumulated several evidence in favor of a common underlying mechanism for altered excitability in MCD rodent models, namely an altered neocortical excitation-inhibition (E/I) balance. Our data also indicate that cortical areas surrounding the heterotopia undergo reactive-type changes that severely modify E/I balance and affect neocortical circuitry, thus contributing to epileptogenesis. Our objectives are to precisely identify the seizure-generating zone, to describe its properties and the mechanisms of seizure generation, and to suggest new therapeutic approaches.


Developmental epilepsies and encephalopathies of genetic and viral origins

P Szepetowski (PI) and S Bauer (PI)
With N Burnashev, S Tarhini, E Buhler, PBMC

We aim at studying and at targeting the pathological alterations of genetic or nongenetic origin (e.g. viral infections) that occur early in the developing brain and that may have severe and long-term consequences on brain development and functioning.

Key words

Brain development, Epilepsy, Cerebral Cortex, Malformation of Cortical Development, Neuronal Migration, Animal Models

Experimental approaches

Histological and Neuroanatomical Methods, Cellular and Molecular Biology (RNAi interference, in utero electroporation), Cell and Slice Culture, Extracellular Multi-site Recordings with Microelectrode Arrays, Time-lapse Imaging

Collaborators and past memberss

Collaborators: – Renzo Guerrini (Florence University, Italy), – Massimo Pasqualetti (Pisa University, Italy) – Heiko Luhman (Mainz University, Germany) – Jamel Chelly (Institut Cochin, Paris, France) – William B. Dobyns (University of Chicago, USA) – Rikke S. Moller (University of Copenhagen, Denmark) – Hiroshi Kawasaki (University of Tokyo, Japan) Past members: – James Ackman (Yale University) – Sabrina Khantane (Invitrogen) – Irina Popova – Aurélie Carabalona (Columbia University)


– Communauté Européenne (EC contract number LSH-CT-2006-037315 (EPICURE) FP6 – Thematic priority LIFESCIHEALTH) – ANR: 2006 neurosciences neurologie et phychiatrie (ANR-06-NEURO-008-01 contract number RPV06055ASA) – ANR: 2009 Programme Retour Post-doctorants (contract number RPV09010AAA) to JB Manent – Fondation J Lejeune to JB Manent – FRC Rotary to A Represa – Europe/INSERM/Région PACA – PhD fellowship to A Carabalona

Join our team

Our team has open positions for undergraduate students, PhD students and postdoctoral fellows. Applications should be sent to Carlos Cardoso or Alfonso Represa.

Nos publications

GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.

Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A, Boutry-Kryza N, Salmi M, Tsintsadze T, Addis L, Motte J, Wright S, Tsintsadze V, Michel A, Doummar D, Lascelles K, Strug L, Waters P, de Bellescize J, Vrielynck P, de Saint Martin A, Ville D, Ryvlin P, Arzimanoglou A, Hirsch E, Vincent A, Pal D, Burnashev N, Sanlaville D, Szepetowski P

Nature genetics - Sep 2013

Administration of Drugs Targeting Microglia Improves the Neurodevelopmental Outcome Following Cytomegalovirus Infection of the Rat Fetal Brain.

Cloarec R, Bauer S, Teissier N, Schaller F, Luche H, Courtens S, Salmi M, Pauly V, Bois E, Pallesi-Pocachard E, Buhler E, Michel FJ, Gressens P, Malissen M, Stamminger T, Streblow DN, Bruneau N, Szepetowski P

Frontiers in cellular neuroscience - Jan 2018

A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity.

Devaux J, Abidi A, Roubertie A, Molinari F, Becq H, Lacoste C, Villard L, Milh M, Aniksztejn L

Epilepsia - May 2016

Impaired vocal communication, sleep-related discharges, and transient alteration of slow-wave sleep in developing mice lacking the GluN2A subunit of N-methyl-d-aspartate receptors.

Salmi M, Del Gallo F, Minlebaev M, Zakharov A, Pauly V, Perron P, Pons-Bennaceur A, Corby-Pellegrino S, Aniksztejn L, Lenck-Santini PP, Epsztein J, Khazipov R, Burnashev N, Bertini G, Szepetowski P

Epilepsia - Jul 2019

Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model.

Lozovaya N, Gataullina S, Tsintsadze T, Tsintsadze V, Pallesi-Pocachard E, Minlebaev M, Goriounova NA, Buhler E, Watrin F, Shityakov S, Becker AJ, Bordey A, Milh M, Scavarda D, Bulteau C, Dorfmuller G, Delalande O, Represa A, Cardoso C, Dulac O, Ben-Ari Y, Burnashev N

Nature communications - Jan 2014

Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.

Salmi M, Bruneau N, Cillario J, Lozovaya N, Massacrier A, Buhler E, Cloarec R, Tsintsadze T, Watrin F, Tsintsadze V, Zimmer C, Villard C, Lafitte D, Cardoso C, Bao L, Lesca G, Rudolf G, Muscatelli F, Pauly V, Khalilov I, Durbec P, Ben-Ari Y, Burnashev N, Represa A, Szepetowski P

Brain : a journal of neurology - Aug 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

A glial origin for periventricular nodular heterotopia caused by impaired expression of Filamin-A.

Carabalona A, Beguin S, Pallesi-Pocachard E, Buhler E, Pellegrino C, Arnaud K, Hubert P, Oualha M, Siffroi JP, Khantane S, Coupry I, Goizet C, Gelot AB, Represa A, Cardoso C

Human molecular genetics - Mar 2012

Cell-autonomous and cell-to-cell signalling events in normal and altered neuronal migration.

Manent JB, Beguin S, Ganay T, Represa A

The European journal of neuroscience - Nov 2011

The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission.

Blümcke I, Thom M, Aronica E, Armstrong DD, Vinters HV, Palmini A, Jacques TS, Avanzini G, Barkovich AJ, Battaglia G, Becker A, Cepeda C, Cendes F, Colombo N, Crino P, Cross JH, Delalande O, Dubeau F, Duncan J, Guerrini R, Kahane P, Mathern G, Najm I, Ozkara C, Raybaud C, Represa A, Roper SN, Salamon N, Schulze-Bonhage A, Tassi L, Vezzani A, Spreafico R

Epilepsia - Jan 2011

Spontaneous epileptic manifestations in a DCX knockdown model of human double cortex.

Lapray D, Popova IY, Kindler J, Jorquera I, Becq H, Manent JB, Luhmann HJ, Represa A

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

Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion.

Cardoso C, Boys A, Parrini E, Mignon-Ravix C, McMahon JM, Khantane S, Bertini E, Pallesi E, Missirian C, Zuffardi O, Novara F, Villard L, Giglio S, Chabrol B, Slater HR, Moncla A, Scheffer IE, Guerrini R

Neurology - Mar 2009

Epilepsy and mental retardation limited to females: an under-recognized disorder.

Scheffer IE, Turner SJ, Dibbens LM, Bayly MA, Friend K, Hodgson B, Burrows L, Shaw M, Wei C, Ullmann R, Ropers HH, Szepetowski P, Haan E, Mazarib A, Afawi Z, Neufeld MY, Andrews PI, Wallace G, Kivity S, Lev D, Lerman-Sagie T, Derry CP, Korczyn AD, Gecz J, Mulley JC, Berkovic SF

Brain : a journal of neurology - Apr 2008

Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas.

Royer B, Soares DC, Barlow PN, Bontrop RE, Roll P, Robaglia-Schlupp A, Blancher A, Levasseur A, Cau P, Pontarotti P, Szepetowski P

BMC genetics - Oct 2007

SRPX2 mutations in disorders of language cortex and cognition.

Roll P, Rudolf G, Pereira S, Royer B, Scheffer IE, Massacrier A, Valenti MP, Roeckel-Trevisiol N, Jamali S, Beclin C, Seegmuller C, Metz-Lutz MN, Lemainque A, Delepine M, Caloustian C, de Saint Martin A, Bruneau N, Depétris D, Mattéi MG, Flori E, Robaglia-Schlupp A, Lévy N, Neubauer BA, Ravid R, Marescaux C, Berkovic SF, Hirsch E, Lathrop M, Cau P, Szepetowski P

Human molecular genetics - Apr 2006

An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na(+) current.

Lauxmann S, Boutry-Kryza N, Rivier C, Mueller S, Hedrich UB, Maljevic S, Szepetowski P, Lerche H, Lesca G

Epilepsia - Sep 2013

Genetics of infantile seizures with paroxysmal dyskinesia: the infantile convulsions and choreoathetosis (ICCA) and ICCA-related syndromes.

Rochette J, Roll P, Szepetowski P

Journal of medical genetics - Dec 2008

Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR.

Royer-Zemmour B, Ponsole-Lenfant M, Gara H, Roll P, Lévêque C, Massacrier A, Ferracci G, Cillario J, Robaglia-Schlupp A, Vincentelli R, Cau P, Szepetowski P

Human molecular genetics - Dec 2008

Sushi repeat protein X-linked 2, a novel mediator of angiogenesis.

Miljkovic-Licina M, Hammel P, Garrido-Urbani S, Bradfield PF, Szepetowski P, Imhof BA

FASEB journal : official publication of the Federation of American Societies for Experimental Biology - Dec 2009

A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene.

Schaller F, Watrin F, Sturny R, Massacrier A, Szepetowski P, Muscatelli F

Human molecular genetics - Dec 2010

Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex.

Roll P, Vernes SC, Bruneau N, Cillario J, Ponsole-Lenfant M, Massacrier A, Rudolf G, Khalife M, Hirsch E, Fisher SE, Szepetowski P

Human molecular genetics - Dec 2010

From rolandic epilepsy to continuous spike-and-waves during sleep and Landau-Kleffner syndromes: insights into possible genetic factors.

Rudolf G, Valenti MP, Hirsch E, Szepetowski P

Epilepsia - Aug 2009

Infantile convulsions with paroxysmal dyskinesia (ICCA syndrome) and copy number variation at human chromosome 16p11.

Roll P, Sanlaville D, Cillario J, Labalme A, Bruneau N, Massacrier A, Délepine M, Dessen P, Lazar V, Robaglia-Schlupp A, Lesca G, Jouve E, Rudolf G, Rochette J, Lathrop GM, Szepetowski P

PloS one - Jan 2010

Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures.

Jamali S, Salzmann A, Perroud N, Ponsole-Lenfant M, Cillario J, Roll P, Roeckel-Trevisiol N, Crespel A, Balzar J, Schlachter K, Gruber-Sedlmayr U, Pataraia E, Baumgartner C, Zimprich A, Zimprich F, Malafosse A, Szepetowski P

PloS one - Jan 2010

The role of the urokinase receptor in epilepsy, in disorders of language, cognition, communication and behavior, and in the central nervous system.

Bruneau N, Szepetowski P

Current pharmaceutical design - Jan 2011

Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions.

Lee HY, Huang Y, Bruneau N, Roll P, Roberson ED, Hermann M, Quinn E, Maas J, Edwards R, Ashizawa T, Baykan B, Bhatia K, Bressman S, Bruno MK, Brunt ER, Caraballo R, Echenne B, Fejerman N, Frucht S, Gurnett CA, Hirsch E, Houlden H, Jankovic J, Lee WL, Lynch DR, Mohammed S, Müller U, Nespeca MP, Renner D, Rochette J, Rudolf G, Saiki S, Soong BW, Swoboda KJ, Tucker S, Wood N, Hanna M, Bowcock AM, Szepetowski P, Fu YH, Ptáček LJ

Cell reports - Jan 2012

PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine.

Cloarec R, Bruneau N, Rudolf G, Massacrier A, Salmi M, Bataillard M, Boulay C, Caraballo R, Fejerman N, Genton P, Hirsch E, Hunter A, Lesca G, Motte J, Roubertie A, Sanlaville D, Wong SW, Fu YH, Rochette J, Ptácek LJ, Szepetowski P

Neurology - Nov 2012

GRIN2A mutations cause epilepsy-aphasia spectrum disorders.

Carvill GL, Regan BM, Yendle SC, O'Roak BJ, Lozovaya N, Bruneau N, Burnashev N, Khan A, Cook J, Geraghty E, Sadleir LG, Turner SJ, Tsai MH, Webster R, Ouvrier R, Damiano JA, Berkovic SF, Shendure J, Hildebrand MS, Szepetowski P, Scheffer IE, Mefford HC

Nature genetics - Sep 2013

A subset of genomic alterations detected in rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2.

Dimassi S, Labalme A, Lesca G, Rudolf G, Bruneau N, Hirsch E, Arzimanoglou A, Motte J, de Saint Martin A, Boutry-Kryza N, Cloarec R, Benitto A, Ameil A, Edery P, Ryvlin P, De Bellescize J, Szepetowski P, Sanlaville D

Epilepsia - Feb 2014

Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.

Huguet G, Nava C, Lemière N, Patin E, Laval G, Ey E, Brice A, Leboyer M, Szepetowski P, Gillberg C, Depienne C, Delorme R, Bourgeron T

PloS one - Jan 2014

NMDA receptor subunit mutations in neurodevelopmental disorders.

Burnashev N, Szepetowski P

Current opinion in pharmacology - Dec 2014

Severe phenotypic spectrum of biallelic mutations in PRRT2 gene.

Delcourt M, Riant F, Mancini J, Milh M, Navarro V, Roze E, Humbertclaude V, Korff C, Des Portes V, Szepetowski P, Doummar D, Echenne B, Quintin S, Leboucq N, Singh Amrathlal R, Rochette J, Roubertie A

Journal of neurology, neurosurgery, and psychiatry - Jul 2015

A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels.

Abidi A, Devaux JJ, Molinari F, Alcaraz G, Michon FX, Sutera-Sardo J, Becq H, Lacoste C, Altuzarra C, Afenjar A, Mignot C, Doummar D, Isidor B, Guyen SN, Colin E, De La Vaissière S, Haye D, Trauffler A, Badens C, Prieur F, Lesca G, Villard L, Milh M, Aniksztejn L

Neurobiology of disease - Aug 2015

Magnetofection™ of NMDA Receptor Subunits GluN1 and GluN2A Expression Vectors in Non-Neuronal Host Cells.

Bruneau N, Szepetowski P

Methods in molecular biology (Clifton, N.J.) - Jan 2017

Cytomegalovirus Infection of the Rat Developing Brain In Utero Prominently Targets Immune Cells and Promotes Early Microglial Activation.

Cloarec R, Bauer S, Luche H, Buhler E, Pallesi-Pocachard E, Salmi M, Courtens S, Massacrier A, Grenot P, Teissier N, Watrin F, Schaller F, Adle-Biassette H, Gressens P, Malissen M, Stamminger T, Streblow DN, Bruneau N, Szepetowski P

PloS one -

The conversion of glutamate by glutamine synthase in neocortical astrocytes from juvenile rat is important to limit glutamate spillover and peri/extrasynaptic activation of NMDA receptors.

Trabelsi Y, Amri M, Becq H, Molinari F, Aniksztejn L

Glia - Nov 2016
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