title: Ablation of Newly Generated Hippocampal Granule Cells Has Disease-Modifying Effects in Epilepsy.
abstract: Hippocampal granule cells generated in the weeks before and after an epileptogenic brain injury can integrate abnormally into the dentate gyrus, potentially mediating temporal lobe epileptogenesis. Previous studies have demonstrated that inhibiting granule cell production before an epileptogenic brain insult can mitigate epileptogenesis. Here, we extend upon these findings by ablating newly generated cells after the epileptogenic insult using a conditional, inducible diphtheria-toxin receptor expression strategy in mice. Diphtheria-toxin receptor expression was induced among granule cells born up to 5 weeks before pilocarpine-induced status epilepticus and these cells were then eliminated beginning 3 d after the epileptogenic injury. This treatment produced a 50% reduction in seizure frequency, but also a 20% increase in seizure duration, when the animals were examined 2 months later. These findings provide the first proof-of-concept data demonstrating that granule cell ablation therapy applied at a clinically relevant time point after injury can have disease-modifying effects in epilepsy.
  
  
  
  These findings support the long-standing hypothesis that newly generated dentate granule cells are pro-epileptogenic and contribute to the occurrence of seizures. This work also provides the first evidence that ablation of newly generated granule cells can be an effective therapy when begun at a clinically relevant time point after an epileptogenic insult. The present study also demonstrates that granule cell ablation, while reducing seizure frequency, paradoxically increases seizure duration. This paradoxical effect may reflect a disruption of homeostatic mechanisms that normally act to reduce seizure duration, but only when seizures occur frequently.
authors: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, and.|Neuroscience Graduate Program, University of Cincinnati, Cincinnati, Ohio 45267.
authors: Bethany E
authors: 0000-0002-2765-419X
authors: BE
authors: Hosford
authors: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, and.
authors: John P
authors: JP
authors: Liska
authors: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, and steve.danzer@cchmc.org.|Department of Anesthesia.|Department of Pediatrics, and.|Neuroscience Graduate Program, University of Cincinnati, Cincinnati, Ohio 45267.
authors: Steve C
authors: 0000-0003-4405-2999
authors: SC
authors: Danzer
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D018891:Dentate Gyrus / Q000473:pathology*; D018450:Disease Progression; D004827:Epilepsy / Q000473:pathology*; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology*
chemical_list: D066257:Heparin-binding EGF-like Growth Factor
keywords: cell ablation; dentate granule cell; diphtheria toxin receptor; epilepsy; neurogenesis; seizure duration