Abstract
A population of neural stem cells (NSCs) dwelling in the dentate gyrus (DG) is able to generate neurons throughout adult life in the hippocampus of most mammals. These NSCs generate also astrocytes naturally and are capable of generating oligodendrocytes after gene manipulation. It has been more recently shown that adult hippocampal NSCs after epileptic seizures as well as subventricular zone NSCs after stroke can give rise to reactive astrocytes (RAs). In the hippocampus, the induction of seizures triggers the conversion of NSCs into reactive NSCs (React-NSCs) characterized by a drastic morphological transformation, abnormal migration, and massive activation or entry into the cell cycle to generate more React-NSCs that ultimately differentiate into RAs. In the search for tools to investigate the properties of React-NSCs, we have explored the LPA1–green fluorescent protein (GFP) transgenic line of mice in which hippocampal NSCs are specifically labeled due to the expression of lysophosphatidic acid receptor 1 (LPA1). We first addressed the validity of the transgene expression as true marker of LPA1 expression and then demonstrated how, after seizures, LPA1-GFP labeled exclusively React-NSCs for several weeks. Then React-NSCs lost LPA1-GFP expression as neurons of the granule cell layer started to express it. Finally, we used knockout for LPA1 transgenic mice to show that LPA1 plays a functional role in the activation of React-NSCs. Thus, we confirmed that LPA1-GFP expression is a valid tool to study both NSCs and React-NSCs and that the LPA1 pathway could be a target in the intent to preserve NSCs after seizures.
Highlights
New neurons are generated postnatally and into adulthood in the dentate gyrus (DG) of the hippocampus of the majority of mammals (Altman and Das, 1965; Bonfanti and Peretto, 2011)
No other cell type expressed lysophosphatidic acid receptor 1 (LPA1)-green fluorescent protein (GFP) in the hippocampus. These results are in agreement with an aging-related study in which we tested the expression of the LPA1 protein in 8 month-old nestin-GFP mice and showed that more than 90% of nestin-GFP+/glial fibrillary acidic protein (GFAP)+ neural stem cells (NSCs) costained with the anti-LPA1 antibody (Martín-Suárez et al, 2019)
We analyzed the expression of LPA1-GFP in early postnatal and young mice and found that LPA1 is absent from radial nestin-expressing NSCs located in subgranular zone (SGZ) and granule cell layer (GCL) in newborn mice, starting in postnatal day 4 (P4), but its expression increased gradually over time until it was present in the vast majority of them by P14 (Supplementary Figures 1A,B)
Summary
New neurons are generated postnatally and into adulthood in the dentate gyrus (DG) of the hippocampus of the majority of mammals (Altman and Das, 1965; Bonfanti and Peretto, 2011). Adult hippocampal neurogenesis (AHN) is maintained, thanks to a population of astrocyte-like and radial glia-like neural stem cells (NSCs) with neurogenic (Seri et al, 2001) and gliogenic potential. Because gliogenic or neurogenic differentiation following entry into the cell cycle is the main factor driving the depletion of the NSC pool (Bonaguidi et al, 2011; Encinas et al, 2011; Pilz et al, 2018), regulation of the quiescence/activation equilibrium is key to sustained neurogenesis throughout adulthood as self-renewing symmetric division does not compensate exhaustion in vivo (Bonaguidi et al, 2011; Pilz et al, 2018). Neuronal activity tightly regulates NSC activation through excitatory and inhibitory neuronal input to NSCs (Song et al, 2012; Yeh et al, 2018)
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