title: Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice.
abstract: OBJECTIVE
  Increased activity of mTOR Complex 1 (mTORC1) has been demonstrated in cortical dysplasia and tuberous sclerosis complex, as well as in animal models of epilepsy. Recent studies in such models revealed that inhibiting mTORC1 with rapamycin effectively suppressed seizure activity. However, seizures can recur after treatment cessation, and continuous rapamycin exposure can adversely affect animal growth and health. Here, we evaluated the efficacy of an intermittent rapamycin treatment protocol on epilepsy progression using neuron subset-specific-Pten (NS-Pten) conditional knockout mice.
  
  
  METHODS
  NS-Pten knockouts were treated with a single course of rapamycin during postnatal weeks 4 and 5, or intermittently over a period of 5 months. Epileptiform activity was monitored using video-electroencephalography (EEG) recordings, and mossy fiber sprouting was evaluated using Timm staining. Survival and body weight were assessed in parallel.
  
  
  RESULTS
  NS-Pten knockouts treated with a single course of rapamycin had recurrence of epilepsy 4-7 weeks after treatment ended. In contrast, epileptiform activity remained suppressed, and survival increased if knockout mice received additional rapamycin during weeks 10-11 and 16-17. Aberrant mossy fiber sprouting, present by 4 weeks of age and progressing in parallel with epileptiform activity, was also blocked by rapamycin.
  
  
  CONCLUSIONS
  These findings demonstrate that a single course of rapamycin treatment suppresses epileptiform activity and mossy fiber sprouting for several weeks before epilepsy recurs. However, additional intermittent treatments with rapamycin prevented this recurrence and enhanced survival without compromising growth. Therefore, these studies add to the growing body of evidence implicating an important role for mTORC1 signaling in epilepsy.
authors.affiliation: The Cain Foundation Laboratories and The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: C Nicole
authors.initials: CN
authors.lastname: Sunnen
authors.forename: Amy L
authors.initials: AL
authors.lastname: Brewster
authors.forename: Joaquin N
authors.initials: JN
authors.lastname: Lugo
authors.forename: Fabiola
authors.initials: F
authors.lastname: Vanegas
authors.forename: Eric
authors.initials: E
authors.lastname: Turcios
authors.forename: Shivani
authors.initials: S
authors.lastname: Mukhi
authors.forename: Deena
authors.initials: D
authors.lastname: Parghi
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Arcangelo
authors.forename: Anne E
authors.initials: AE
authors.lastname: Anderson
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology; D018450:Disease Progression; D004569:Electroencephalography; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D008297:Male; D051379:Mice; D009412:Nerve Fibers / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus