title: High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy.
abstract: OBJECTIVE
  The role of granule cell axon (mossy fiber) sprouting in temporal lobe epileptogenesis is unclear and controversial. Rapamycin suppresses mossy fiber sprouting, but its reported effects on seizure frequency are mixed. The present study used high-dose rapamycin to more completely block mossy fiber sprouting and to measure the effect on seizure frequency.
  
  
  METHODS
  Mice were treated with pilocarpine to induce status epilepticus. Beginning 24 h later and continuing for 2 months, vehicle or rapamycin (10 mg/kg/day) was administered. Starting 1 month after status epilepticus, mice were monitored by video 9 h per day, every day, for 1 month to measure the frequency of spontaneous motor seizures. At the end of seizure monitoring, a subset of mice was prepared for anatomic analysis. Mossy fiber sprouting was measured as the proportion of the granule cell layer and molecular layer that displayed black labeling in Timm-stained sections.
  
  
  RESULTS
  Extensive mossy fiber sprouting developed in mice that experienced status epilepticus and were treated with vehicle. In rapamycin-treated mice, mossy fiber sprouting was blocked almost to the level of naive controls. Seizure frequency was similar in vehicle-treated and rapamycin-treated mice.
  
  
  CONCLUSIONS
  These findings suggest that mossy fiber sprouting is not necessary for epileptogenesis in the mouse pilocarpine model. They also reveal that rapamycin does not have antiseizure or antiepileptogenic effects in this model.
authors.affiliation: Department of Comparative Medicine, Stanford University, Stanford, California 94305-5342, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Heng
authors.forename: Megan M
authors.initials: MM
authors.lastname: Haney
authors.forename: Paul S
authors.initials: PS
authors.lastname: Buckmaster
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy*; D005260:Female; D008297:Male; D051379:Mice; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D010862:Pilocarpine / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D010862:Pilocarpine; D020123:Sirolimus
keywords: Axon sprouting; Dentate gyrus; Granule cells; Hilar neurons; Pilocarpine; Timm stain