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.

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