title: TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice.
abstract: OBJECTIVE
  Seizure development in tuberous sclerosis complex (TSC) correlates with the presence of specific lesions called cortical tubers. Moreover, heterozygous TSC animal models do not show gross brain pathology and are seizure-free, suggesting that such pathology is a prerequisite for the development of epilepsy. However, cells within TSC lesions show increased activity of the target of rapamycin complex 1 (TORC1) pathway, and recent studies have implicated this pathway in non-TSC-related animal models of epilepsy and neuronal excitability. These findings imply a direct role for TORC1 in epilepsy. Here, we investigate the effect of increased TORC1 signaling induced by acute biallelic deletion of Tsc1 in healthy adult mice.
  
  
  METHODS
  Biallelic Tsc1 gene deletion was induced in adult Tsc1 heterozygous and wild-type mice. Seizures were monitored by electroencephalographic and video recordings. Molecular and cellular changes were investigated by Western blot analysis, immunohistochemistry, and electrophysiology.
  
  
  RESULTS
  Mice developed epilepsy a few days after biallelic Tsc1 deletion. Acute gene deletion was not accompanied by any obvious histological changes, but resulted in activation of the TORC1 pathway, enhanced neuronal excitability, and a decreased threshold for protein-synthesis-dependent long-term potentiation preceding the onset of seizures. Rapamycin treatment after seizure onset reduced TORC1 activity and fully abolished the seizures.
  
  
  CONCLUSIONS
  Our data indicate a direct role for TORC1 signaling in epilepsy development, even in the absence of major brain pathology. This suggests that TORC1 is a promising target for treating seizures not only in TSC but also in other forms of epilepsy that result from increased TORC1 activation.
authors.affiliation: Department of Neuroscience, Erasmus University Medical Center, Rotterdam, the Netherlands; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Abs
authors.forename: Susanna M I
authors.initials: SM
authors.lastname: Goorden
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Schreiber
authors.forename: Iris E
authors.initials: IE
authors.lastname: Overwater
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Bruinsma
authors.forename: Elvedin
authors.initials: E
authors.lastname: Aganović
authors.forename: Nils Z
authors.initials: NZ
authors.lastname: Borgesius
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.forename: Ype
authors.initials: Y
authors.lastname: Elgersma
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D005786:Gene Expression Regulation / Q000235:genetics*; D006624:Hippocampus / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics*; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; C504241:RHEBL1 protein, human; D011960:Receptors, Estrogen; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C010140:estrophilin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; D020123:Sirolimus