Abstract

Aberrant integration of newborn hippocampal granule cells is hypothesized to contribute to the development of temporal lobe epilepsy. To test this hypothesis, we used a diphtheria toxin receptor expression system to selectively ablate these cells from the epileptic mouse brain. Epileptogenesis was initiated using the pilocarpine status epilepticus model in male and female mice. Continuous EEG monitoring was begun 2–3 months after pilocarpine treatment. Four weeks into the EEG recording period, at a time when spontaneous seizures were frequent, mice were treated with diphtheria toxin to ablate peri-insult generated newborn granule cells, which were born in the weeks just before and after pilocarpine treatment. EEG monitoring continued for another month after cell ablation. Ablation halted epilepsy progression relative to untreated epileptic mice; the latter showing a significant and dramatic 300% increase in seizure frequency. This increase was prevented in treated mice. Ablation did not, however, cause an immediate reduction in seizures, suggesting that peri-insult generated cells mediate epileptogenesis, but that seizures per se are initiated elsewhere in the circuit. These findings demonstrate that targeted ablation of newborn granule cells can produce a striking improvement in disease course, and that the treatment can be effective when applied months after disease onset.

Highlights

  • Aberrant integration of newborn hippocampal dentate granule cells is implicated in temporal lobe epileptogenesis

  • Three-week-old NestinCreERT2; GFP+; DTrfl/wt [DTr-expressing] and NestinCreERT2; GFP+; DTrwt/wt [DTr-negative] mice were treated with tamoxifen to induce diphtheria toxin receptor (DTr) expression in newborn granule cells

  • We used a targeted cell ablation strategy to demonstrate that selective removal of peri-insult generated newborn granule cells from the epileptic brain prevents further epilepsy progression

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Summary

Introduction

Aberrant integration of newborn hippocampal dentate granule cells is implicated in temporal lobe epileptogenesis. The efficacy of ablating newborn granule cells after seizure onset, had not been assessed. It is important to determine whether newborn granule cells still play a role after epilepsy onset, or whether their impact is limited to the prodromal phase of epileptogenesis. To determine whether eliminating newborn granule cells would be therapeutic in animals with established epilepsy, we used a transgenic mouse model system to express the diphtheria toxin receptor (DTr) in peri-insult generated newborn granule cells. This approach allowed us to ablate these same neurons months after the development of epilepsy by treating the animals with diphtheria toxin (DT)

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