Ablation of Newly Generated Hippocampal Granule Cells Has Disease-Modifying Effects in Epilepsy
| Autor: | Steve C. Danzer, John P. Liska, Bethany E. Hosford |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Cell Survival Receptor expression Mice Transgenic Status epilepticus Hippocampal formation Epileptogenesis Mice 03 medical and health sciences Epilepsy 0302 clinical medicine medicine Animals Neurons business.industry General Neuroscience Dentate gyrus Neurogenesis Granule cell medicine.disease Current Literature in Basic Science Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Dentate Gyrus Disease Progression Female medicine.symptom business Neuroscience 030217 neurology & neurosurgery Heparin-binding EGF-like Growth Factor |
| Zdroj: | The Journal of Neuroscience. 36:11013-11023 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | 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.SIGNIFICANCE STATEMENTThese 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. |
| Databáze: | OpenAIRE |
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