Functional and morphological characterization of neural stem cells in murine models of neuronal hyperexcitation

Abstract

Adult hippocampal neurogenesis, even though it has been controversial for a very long time, persists in the brain of most mammal species during postnatal and adult life. Under physiologic conditions, neurogenesis is an extremely regulated multi-step process where Neural Stem Cells (NSCs) get activated continuously but with low frequency, and then divide giving rise to amplifying neural progenitors (ANPs) which proliferate for a few days and then die by apoptosis, being removed by microglia; or continue their neurogenic pathway, maturing into post-mitotic neuroblasts that differentiate into new neurons. Any possible alteration, such as neuronal hyperexcitation, can trickle down the neurogenic cascade. Neurogenic alterations have been reported as a hallmark in several neurodegenerative diseases as epilepsy. Epileptic symptoms are widely range, from convulsive to non-convulsive seizures, possible granule cell dispersion (GCD) or astrogliosis. Neuronal activity levels may vary between patients. Here, by KA-induced epilepsy murine models, we hypothesized that different levels of neuronal activity will trigger differential response on NSCs. In order to answer this question our current efforts are now focused on establishing mice models replicating the human natural course of hyperexcitation conditions by standardizing a reliable model of epileptiform activity (EA) and mesial temporal lobe epilepsy (MTLE) with mild sclerosis to investigate its effects on a hippocampal neurogenic niche. We explored the divergent impacts of increased neuronal hyperexcitation induced by intrahippocampal kainic acid (KA) injections (0.74 mM and 2.22 mM) in 3-month-old mice, modelling Epileptiform Activity (LKA or EA) and Mesial Temporal Lobe Epilepsy (MTLE). As expected, different KA doses cause distinct cellular response in the neurogenesis niche in DG. Moreover, the morphologic changes that NSCs suffer when exposed to KA are caused by enhanced neuronal activity thus the higher KA dose, the higher cell complexity and the larger morphologic changes.