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

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

doi:10.1038/ncomms5563

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

Nat Commun. 2014 Aug 1:5:4563. doi: 10.1038/ncomms5563.

Authors

N Lozovaya¹, S Gataullina¹, T Tsintsadze², V Tsintsadze³, E Pallesi-Pocachard³, M Minlebaev⁴, N A Goriounova³, E Buhler³, F Watrin³, S Shityakov⁵, A J Becker⁶, A Bordey⁷, M Milh⁸, D Scavarda⁸, C Bulteau⁹, G Dorfmuller⁹, O Delalande¹⁰, A Represa³, C Cardoso³, O Dulac¹¹, Y Ben-Ari³, N Burnashev³

Affiliations

¹ 1] INSERM U901, INMED, Parc Scientifique et Technologique de Luminy 163, route de Luminy-BP 13, 13273 Marseille Cedex 09, France [2] UMR901, Aix-Marseille University, 58 Boulevard Charles Livon, 13284 Marseille, France [3] INSERM U1129; University Paris Descartes, CEA, Gif sur Yvette, 149 Rue de Sèvres, 75015 Paris, France [4].
² 1] INSERM U901, INMED, Parc Scientifique et Technologique de Luminy 163, route de Luminy-BP 13, 13273 Marseille Cedex 09, France [2] UMR901, Aix-Marseille University, 58 Boulevard Charles Livon, 13284 Marseille, France [3].
³ 1] INSERM U901, INMED, Parc Scientifique et Technologique de Luminy 163, route de Luminy-BP 13, 13273 Marseille Cedex 09, France [2] UMR901, Aix-Marseille University, 58 Boulevard Charles Livon, 13284 Marseille, France.
⁴ 1] INSERM U901, INMED, Parc Scientifique et Technologique de Luminy 163, route de Luminy-BP 13, 13273 Marseille Cedex 09, France [2] UMR901, Aix-Marseille University, 58 Boulevard Charles Livon, 13284 Marseille, France [3] Laboratory of Neurobiology, Kazan Federal University, Kremlevskaya street 18, 420000 Kazan, Russia.
⁵ Department of Anaesthesia and Critical Care, University of Würzburg, Josef-Schneider-Street 2, 97080 Würzburg, Germany.
⁶ Department of Neuropathology, University of Bonn Medical Center, Sigmund Freud Street 25, D-53105 Bonn, Germany.
⁷ Neurosurgery, and Cellular and Molecular Physiology Departments, Yale University School of Medicine, PO Box 208082, New Haven, Connecticut 06520-8082, USA.
⁸ APHM, Department of Pediatric Neurosurgery and Neurology, CHU Timone, 264 Rue Saint-Pierre, 13385 Marseille Cedex 5, France.
⁹ 1] INSERM U1129; University Paris Descartes, CEA, Gif sur Yvette, 149 Rue de Sèvres, 75015 Paris, France [2] Department of Pediatric Neurosurgery, Foundation Rothschild, 29 Rue Manin, 75019 Paris, France.
¹⁰ Department of Pediatric Neurosurgery, Foundation Rothschild, 29 Rue Manin, 75019 Paris, France.
¹¹ 1] INSERM U1129; University Paris Descartes, CEA, Gif sur Yvette, 149 Rue de Sèvres, 75015 Paris, France [2] Department of Pediatric Neurosurgery, Foundation Rothschild, 29 Rue Manin, 75019 Paris, France [3] APHP, Necker Hospital, 149 Rue de Sèvres, 75015 Paris, France.

Abstract

Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote Tsc1(+/-) mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (<P19). Seizures are generated intracortically in the granular layer of the neocortex. Slow kinetics of aberrant GluN2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in Tsc1(+/-) mice in vivo and in vitro. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Animals
Anticonvulsants / pharmacology*
Disease Models, Animal
Electroencephalography
Epilepsy / drug therapy*
Epilepsy / genetics
Epilepsy / metabolism
Epilepsy / pathology
Gene Expression Regulation
Heterozygote
Humans
Male
Mice
Mice, Transgenic
Microtomy
Neocortex / drug effects
Neocortex / metabolism
Neocortex / pathology
Patch-Clamp Techniques
Pyrazoles / pharmacology*
Quinolones / pharmacology*
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
Receptors, N-Methyl-D-Aspartate / genetics
Receptors, N-Methyl-D-Aspartate / metabolism
Signal Transduction
TOR Serine-Threonine Kinases / genetics*
TOR Serine-Threonine Kinases / metabolism
Tissue Culture Techniques
Tuberous Sclerosis / drug therapy*
Tuberous Sclerosis / genetics
Tuberous Sclerosis / metabolism
Tuberous Sclerosis / pathology
Tuberous Sclerosis Complex 1 Protein
Tumor Suppressor Proteins / deficiency
Tumor Suppressor Proteins / genetics*

Substances

4-(5-(4-bromophenyl)-3-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
Anticonvulsants
NR2C NMDA receptor
Pyrazoles
Quinolones
Receptors, N-Methyl-D-Aspartate
TSC1 protein, human
Tsc1 protein, mouse
Tuberous Sclerosis Complex 1 Protein
Tumor Suppressor Proteins
mTOR protein, mouse
TOR Serine-Threonine Kinases