Reactive Disruption of the Hippocampal Neurogenic Niche After Induction of Seizures by Injection of Kainic Acid in the Amygdala.

Teresa Muro-García,Lara Galbarriatu,Roberto Valcárcel-Martín,Amanda Sierra,Pablo Fuentealba,Juan Manuel Encinas,Ainhoa Marinas,Nelson Espinosa,Soraya Martín-Suárez,Laura Zaldumbide

doi:10.3389/fcell.2019.00158

Abstract

Adult neurogenesis persists in the adult hippocampus due to the presence of multipotent neural stem cells (NSCs). Hippocampal neurogenesis is involved in a range of cognitive functions and is tightly regulated by neuronal activity. NSCs respond promptly to physiological and pathological stimuli altering their neurogenic and gliogenic potential. In a mouse model of mesial temporal lobe epilepsy (MTLE), seizures triggered by the intrahippocampal injection of the glutamate receptor agonist kainic acid (KA) induce NSCs to convert into reactive NSCs (React-NSCs) which stop producing new neurons and ultimately generate reactive astrocytes thus contributing to the development of hippocampal sclerosis and abolishing neurogenesis. We herein show how seizures triggered by the injection of KA in the amygdala, an alternative model of MTLE which allows parallel experimental manipulation in the dentate gyrus, also trigger the induction of React-NSCs and provoke the disruption of the neurogenic niche resulting in impaired neurogenesis. These results highlight the sensitivity of NSCs to the surrounding neuronal circuit activity and demonstrate that the induction of React-NSCs and the disruption of the neurogenic niche are not due to the direct effect of KA in the hippocampus. These results also suggest that neurogenesis might be lost in the hippocampus of patients with MTLE. Indeed we provide results from human MTLE samples absence of cell proliferation, of neural stem cell-like cells and of neurogenesis.

Highlights

In the hippocampus of most mammals, including humans (Eriksson et al, 1998; Moreno-Jiménez et al, 2019), neurogenesis continues postnatally (Altman and Das, 1965) and throughout adulthood due to the existence of a population of neural stem cells (NSCs) with neurogenic (Seri et al, 2001) and gliogenic potential (Encinas et al, 2011)
After seizures NSCs transform into reactive NSCs (React-NSCs) and later into reactive astrocytes that contribute to hippocampal sclerosis, a pathological hallmark of mesial temporal lobe epilepsy (MTLE) consisting of neuronal death and reactive gliosis
We had shown before that seizures induced in an experimental model of MTLE by intrahippocampal injection of MTLE have a profound effect on NSCs

Summary

Introduction

In the hippocampus of most mammals, including humans (Eriksson et al, 1998; Moreno-Jiménez et al, 2019), neurogenesis continues postnatally (Altman and Das, 1965) and throughout adulthood due to the existence of a population of neural stem cells (NSCs) with neurogenic (Seri et al, 2001) and gliogenic potential (Encinas et al, 2011). As neuronal activity increases above physiological levels in experimental models of electroconvulsive therapy (electroconvulsive shock, ECS) (Segi-Nishida et al, 2008; Jun et al, 2015) or epilepsy (Huttmann et al, 2003; Indulekha et al, 2010) NSCs get activated in increasing numbers which in turn accelerates their depletion in the long term (Sierra et al, 2015) after an initial boost of neurogenesis (Parent et al, 1997). In an experimental model of mesial temporal lobe epilepsy (MTLE), that characterizes by seizures being originated in the hippocampus and related structures, NSCs undergo a profound alteration of their neurogenic program. We wondered how NSCs and the neurogenic cascade would be affected in an alternative model of MTLE (aMTLE) based on the intra-amygdalar injection of KA (Mouri et al, 2008). We showed that in a similar fashion to what we found in the mouse models of MTLE, cell proliferation and neurogenesis are lost in the hippocampus of MTLE patients

Methods

Results

Conclusion