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.

Reduced abnormal integration of adult-generated granule cells does not attenuate spontaneous recurrent seizures in mice

“…An overall decrease of subsequent abnormal integrations was found at 6 weeks after the cell ablation before and after SE Considering developmental time window for the abnormal integrations is at least 4 weeks, even longer for the granule cells projecting their axons to the IML (Kron et al, 2010), we therefore chose the time point of 6 weeks after the last MAM injection (10 weeks after SE) to examine the abnormal integrations of adult-generated granule cells. Using Prox 1 staining, we first demonstrated that ablation of newborn cells 4 weeks before and after SE reduced hilar ectopic granule cells, which is consistent with other studies (Cho et al, 2015;Hosford et al, 2016;Jung et al, 2004). Next, we showed an effective blockage of axon sprouting into the IML using Timm staining.…”

“…Next, we showed an effective blockage of axon sprouting into the IML using Timm staining. Given the unchanged MFS in other studies (Cho et al, 2015;Hosford et al, 2016;Jung et al, 2004), the current findings therefore strongly suggest that ablating overall newborn granule cells, but not targeting a subset of them may be required to significantly block the subsequent formation of axon sprouting. Also, it seems plausible that a later time point after SE for morphological observation, i.e.…”

“…If it is true that distinct subpopulations of newly generated granule cells and subsequent abnormal integrations make different, and perhaps opposing, contributions to epileptogenesis, the contrasting findings in this and other papers (Jung et al, 2004(Jung et al, , 2006Sugaya et al, 2010;Cho et al, 2015;Hosford et al, 2016) are not difficult to explain: the attenuated SRSs may be attributed to the elimination of a cohort of newborn cells with hilar ectopic migration, which was identified in their studies. An alternative possibility is that reduced neurogenesis, rather than selective removal of abnormal cells, is critical for the observed effect.…”

“…In the papers by Cho et al (2015), Hosford et al (2016), and Jung et al (2004), the numbers of HECs were reduced by cell ablation treatments, while no any change on MFS was found. Papers by Jung et al (2006), Sugaya et al (2010) and Pekcec et al (2007) demonstrated a reduction in HECs after ablation of hippocampal neurogenesis, but MSF was not measured.…”

“…However, studies on whether aberrant hippocampal neurogenesis contribute to epileptogenesis have produced mixed results. Some studies using pharmacological agents (Jung et al, 2004(Jung et al, , 2006Sugaya et al, 2010) or genetic approaches (Cho et al, 2015;Hosford et al, 2016) concluded that inhibiting the newborn granule cells leaded to reduced spontaneous recurrent seizures (SRSs), while others indicated that ablation of newborn granule cells via pharmacological agents (Radley and Jacobs, 2003;Pekcec et al, 2008) or selective hippocampal irradiation (Pekcec et al, 2011) did not alleviate chronic seizures.…”