Ablation of peri-insult generated granule cells after epilepsy onset halts disease progression.

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.

Ablation of Newly Generated Hippocampal Granule Cells Has Disease-Modifying Effects in Epilepsy.

Unlabelled: 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.

Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain.

Growing evidence implicates the dentate gyrus in temporal lobe epilepsy (TLE). Dentate granule cells limit the amount of excitatory signaling through the hippocampus and exhibit striking neuroplastic changes that may impair this function during epileptogenesis. Furthermore, aberrant integration of newly-generated granule cells underlies the majority of dentate restructuring.

Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy.

The dentate gyrus is hypothesized to function as a "gate," limiting the flow of excitation through the hippocampus. During epileptogenesis, adult-generated granule cells (DGCs) form aberrant neuronal connections with neighboring DGCs, disrupting the dentate gate. Hyperactivation of the mTOR signaling pathway is implicated in driving this aberrant circuit formation.