Abstract
Hippocampal neurogenesis, the process by which neural stem cells (NSCs) continuously generate new neurons in the dentate gyrus (DG) of most mammals including humans, is chiefly regulated by neuronal activity. Thus, severe alterations have been found in samples from epilepsy patients and in the hippocampal neurogenic niche in mouse models of epilepsy. Reactive-like and gliogenic NSCs plus aberrant newborn neurons with altered migration, morphology, and functional properties are induced by seizures in experimental models of temporal lobe epilepsy. Hippocampal neurogenesis participates in memory and learning and in the control of anxiety and stress. It has been therefore hypothesized that part of the cognitive symptoms associated with epilepsy could be promoted by impaired hippocampal neurogenesis. We here analyze for the first time the alterations of the neurogenic niche in a novel mouse model of Dravet syndrome (DS), a genetic encephalopathy with severe epilepsy in infancy and multiple neurological comorbidities. Scn1aWT/A1783V mice, hereafter referred to as DS, carrying a heterozygous and clinically relevant SCN1A mutation (A1783V) recapitulate the disease at the genetic and phenotypic levels. We demonstrate that in the neurogenic niche of young adult DS mice there are fewer NSCs, they have impaired cell division and bear reactive-like morphology. In addition, there is significant aberrant neurogenesis. Newborn immature neurons migrate abnormally, and several morphological features are drastically changed. Thus, this study shows for the first time important modifications in hippocampal neurogenesis in DS and opens venues for further research on this topic.
Highlights
The hippocampus is one of the most vulnerable structures of the brain to excitotoxicity and to seizures due to its recurrent circuits
We co-stained brain slices from 7-week-old WT or Dravet syndrome (DS) mice with antibodies against GFAP, which is expressed by both astrocytes and neural stem cells (NSCs), and against S100β, which is present in astrocytes and reactive astrocytes (RAs) but not in NSCs (Figure 1A)
NSCs in the DS mice had clearly altered morphology with significantly higher complexity (Figure 1D and Supplementary Figure S1A). These results suggest that to what is found in adult mouse models of mesial temporal lobe epilepsy (MTLE), NSCs develop a reactive morphology in DS
Summary
The hippocampus is one of the most vulnerable structures of the brain to excitotoxicity and to seizures due to its recurrent circuits. Excitotoxicity and seizures impair AHN with several consequences: (a) the neurons lost by excitotoxicity cannot be regenerated; (b) the normal functions of AHN are disrupted; and (c) the normally neurogenic neural stem cells (NSCs) of the hippocampus turn to participate in reactive gliogenesis. The persistence of AHN in the dentate gyrus (DG) of the Hippocampal Neurogenesis in Dravet Syndrome hippocampus is consequence of a population of NSCs with neurogenic (Seri et al, 2001) and gliogenic capacity (Encinas et al, 2011). After being activated to generate neuronal precursors, NSCs undergo ultimate gliogenic (Bonaguidi et al, 2011; Encinas et al, 2011) or neurogenic (Pilz et al, 2018) differentiation. The population of NSCs gets depleted overtime in an activation-dependent manner so that the population, and AHN, is maximal during the postnatal-juvenile period, and is minimal in the aged brain (Sorrells et al, 2018)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
