RT Journal Article
SR Electronic
T1 Clonal analysis of newborn hippocampal dentate granule cell proliferation and development in temporal lobe epilepsy
JF eneuro
JO eneuro
FD Society for Neuroscience
SP ENEURO.0087-15.2015
DO 10.1523/ENEURO.0087-15.2015
A1 Shatrunjai P. Singh
A1 Candi L. LaSarge
A1 Amen An
A1 John J. McAuliffe
A1 Steve C. Danzer
YR 2015
UL http://www.eneuro.org/content/early/2015/12/24/ENEURO.0087-15.2015.abstract
AB 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 two 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 micro-environments 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. Taken together, these findings strongly predict that distinct mechanisms regulate different aspects of granule cell pathology in epilepsy.Significance Statement Epileptogenic injuries disrupt adult neurogenesis, leading to the abnormal integration of adult-generated granule cells. The newborn cells exhibit a variety of pathologies, including dendritic abnormalities and migration defects. It was not known, however, whether all progenitors contributed equally to the accumulation of these abnormal cells or whether a distinct subset of progenitors was responsible. Here, we performed a clonal analysis study of progenitor cell activity following status epilepticus. Our results reveal that a small subset of progenitors produces the majority of ectopic granule cells, while cells with abnormal dendrites arise ubiquitously throughout the progenitor pool. Together, these findings demonstrate a newly-understood complexity among progenitors in producing abnormal granule cells in epilepsy.