Clonal analysis of newborn hippocampal dentate granule cell proliferation and development in temporal lobe epilepsy

TL;DR

This study used clonal analysis in mice to determine that a small subset of progenitors mainly produce ectopic hippocampal granule cells after epilepsy-inducing injury, revealing targeted pathological processes.

Contribution

It demonstrates that specific progenitors are responsible for abnormal cell proliferation in epilepsy, highlighting potential targeted mechanisms of disease development.

Findings

Few progenitors generate most ectopic cells post-epilepsy induction.

Basal dendrite abnormalities are evenly distributed among progenitors.

Global factors influence dendritic development independently of progenitor origin.

Abstract

Hippocampal dentate granule cells are among the few neuronal cell types generated throughout adult life in mammals. In the normal brain, new granule cells are generated from progenitors in the subgranular zone and integrate in a typical fashion. During the development of epilepsy, granule cell integration is profoundly altered. The new cells migrate to ectopic locations and develop misoriented basal dendrites. Although it has been established that these abnormal cells are newly generated, it is not known whether they arise ubiquitously throughout the progenitor cell pool or are derived from a smaller number of bad actor progenitors. To explore this question, we conducted a clonal analysis study in mice expressing the Brainbow fluorescent protein reporter construct in dentate granule cell progenitors. Mice were examined 2 months after pilocarpine-induced status epilepticus, a treatment that leads to the development of epilepsy. Brain sections were rendered translucent so that entire hippocampi could be reconstructed and all fluorescently labeled cells identified. Our findings reveal that a small number of progenitors produce the majority of ectopic cells following status epilepticus, indicating that either the affected progenitors or their local microenvironments have become pathological. By contrast, granule cells with basal dendrites were equally distributed among clonal groups. This indicates that these progenitors can produce normal cells and suggests that global factors sporadically disrupt the dendritic development of some new cells. Together, these findings strongly predict that distinct mechanisms regulate different aspects