title: Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model.
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.
authors: 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].
authors: N
authors: N
authors: Lozovaya
authors: 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].
authors: S
authors: S
authors: Gataullina
authors: 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].
authors: T
authors: T
authors: Tsintsadze
authors: 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.
authors: V
authors: V
authors: Tsintsadze
authors: 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.
authors: E
authors: E
authors: Pallesi-Pocachard
authors: 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.
authors: M
authors: M
authors: Minlebaev
authors: 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.
authors: N A
authors: NA
authors: Goriounova
authors: 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.
authors: E
authors: E
authors: Buhler
authors: 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.
authors: F
authors: F
authors: Watrin
authors: Department of Anaesthesia and Critical Care, University of Würzburg, Josef-Schneider-Street 2, 97080 Würzburg, Germany.
authors: S
authors: S
authors: Shityakov
authors: Department of Neuropathology, University of Bonn Medical Center, Sigmund Freud Street 25, D-53105 Bonn, Germany.
authors: A J
authors: AJ
authors: Becker
authors: Neurosurgery, and Cellular and Molecular Physiology Departments, Yale University School of Medicine, PO Box 208082, New Haven, Connecticut 06520-8082, USA.
authors: A
authors: A
authors: Bordey
authors: APHM, Department of Pediatric Neurosurgery and Neurology, CHU Timone, 264 Rue Saint-Pierre, 13385 Marseille Cedex 5, France.
authors: M
authors: M
authors: Milh
authors: APHM, Department of Pediatric Neurosurgery and Neurology, CHU Timone, 264 Rue Saint-Pierre, 13385 Marseille Cedex 5, France.
authors: D
authors: D
authors: Scavarda
authors: 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.
authors: C
authors: C
authors: Bulteau
authors: 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.
authors: G
authors: G
authors: Dorfmuller
authors: Department of Pediatric Neurosurgery, Foundation Rothschild, 29 Rue Manin, 75019 Paris, France.
authors: O
authors: O
authors: Delalande
authors: 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.
authors: A
authors: A
authors: Represa
authors: 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.
authors: C
authors: C
authors: Cardoso
authors: 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.
authors: O
authors: O
authors: Dulac
authors: 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.
authors: Y
authors: Y
authors: Ben-Ari
authors: 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.
authors: N
authors: N
authors: Burnashev
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008867:Microtomy; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D046509:Tissue Culture Techniques; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: C568654:4-(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; D000927:Anticonvulsants; C432823:NR2C NMDA receptor; D011720:Pyrazoles; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases