Neurogenesis and epilepsy

Abstract

SUMMARYPersistent neural stem cells generate dentate granule cells (DGCs) throughout life. Evidence suggests that aberrant neurogenesis contributes to epileptic structural abnormalities, but that normally integrating adult-born DGCs may restore inhibition. Current research focuses on how epileptogenic insults alter neurogenesis, and whether restoring normal neurogenesis will attenuate epi- Persistent neural stem cells (NSCs) in the subgranular zone (SGZ) of the hippocampal dentate gyrus generate dentate granule cells (DGCs) throughout life (Altman & Das, 1965). Many adult-born DGCs integrate into the preexisting circuitry and acquire electrophysiologic characteristics of mature DGCs. Mounting evidence implicates DGC neurogenesis in certain forms of hippocampus-dependent learning and memory and in the modulation of emotional behavior or anxiety. Data from rodent models of medial temporal lobe epilepsy (mTLE) show that prolonged seizures acutely increase adult DGC neurogenesis, but the functional implications of altered neurogenesis in mTLE are poorly understood. Accumulating evidence suggests, however, that altered neurogenesis contributes to several well-characterized cellular abnormalities seen in human and experimental mTLE. These abnormalities include mossy fiber sprouting, DGC layer dispersion, and the appearance of DGCs in ectopic locations or with abnormal hilar basal dendrites (Kron et al., 2010). In contrast, other work suggests that adult-born DGCs that integrate normally during epileptogenesis may serve a compensatory role to restore inhibition (Jakubs et al., 2006).Because adult hippocampal neurogenesis likely underlies specific hippocampus-dependent learning and memory functions, defective neurogenesis may also contribute to the progressive memory dysfunction seen in mTLE. This idea is supported by recent findings that cognitive impairment in an experimental mTLE model decreases when seizure-induced neurogenesis is inhibited with valproic acid, probably via its histone deacetylase inhibitory activity (Jessberger et al., 2007). In addition, DGC neurogenesis is suppressed in the chronic stage of experimental mTLE, raising the possibility that memory function may be impaired both by aberrant neurogenesis and a reduction of normal DGC neurogenesis. Current work aims to define the mechanisms by which epileptogenic insults alter adult neurogenesis, and whether restoring normal NSC behavior after such insults will attenuate the development of epilepsy or its comorbidities. DisclosureThe authors declare no conflicts of interest. References

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

“…The mechanisms by which rapamycin produces these positive effects, however, are unclear. For the present study, we examined several hippocampal abnormalities implicated in the development of temporal lobe epilepsy (Parent and Kron, 2012; Hester and Danzer, 2014), including mossy fiber sprouting (Buckmaster, 2014), hilar ectopic granule cell accumulation (Scharfman and Pierce, 2012), basal dendrite formation (Ribak et al, 2012), reactive astrogliosis and microgliosis (Sharma et al, 2008; Gibbons et al, 2013) and mossy cell loss (Jinde et al, 2013). Consistent with previous studies (Zeng et al, 2009; Buckmaster et al, 2009), we observed a significant reduction in mossy fiber sprouting with rapamycin treatment.…”

Hippocampal injury-induced cognitive and mood dysfunction, altered neurogenesis, and epilepsy: Can early neural stem cell grafting intervention provide protection?

“…While multiple causes have been proposed for SE-induced SRS, its link to hippocampal alterations such as the loss of different subclasses of GABA-ergic interneurons and failure of inhibition [69], persistent neuroinflammation typified by reactive astrocytes and activated microglia [75], and aberrant neurogenesis in the early phase after SE [19,76,77] have received significant support. On the other hand, SE-induced mood and memory dysfunction are likely linked to progressive loss of hippocampal principal neurons (e.g.…”

Kainate-induced epileptogenesis alters circular hole board learning strategy but not the performance of C57BL/6J mice

“…Next to its importance in spatial learning, the hippocampus is also the main target of action for stress hormones [30,53]. The effect of stressors combined with the damage caused by SE [34,54] leads to worse functioning of the hippocampus, which in turn amounts to impaired learning and memory formation. In contrast, low-stress settings, such as the hole board experiments performed here, support that the effects of stress are severe, as no impaired learning and memory were found in these settings [11][12][13] and lower corticosterone levels have been reported after completion of the task.…”

“…All behavioral tasks started 35 days after the induction of SE, with the exception of the elevated plus maze (EPM) task, which took place after the circular hole board (CHB) or modified hole board (MHB) task was completed (on days [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]. In between trials, behavioral setups were cleaned with 0.1% acetic acid to eliminate odor cues.…”