Evidence of Progenitor Cell Lineage Rerouting in the Adult Mouse Hippocampus After Status Epilepticus

Daniela M S Moura,Claudio M Queiroz,Christophe Heinrich,Celia Lentini,Juliana Alves Brandão,Marcos R Costa

doi:10.3389/fnins.2020.571315

Abstract

Cell lineage in the adult hippocampus comprises multipotent and neuron-committed progenitors. In the present work, we fate-mapped neuronal progenitors using Dcx-CreERT2 and CAG-CAT-EGFP double-transgenic mice (cDCX/EGFP). We show that 3 days after tamoxifen-mediated recombination in cDCX/EGFP adult mice, GFP+ cells in the dentate gyrus (DG) co-expresses DCX and about 6% of these cells are proliferative neuronal progenitors. After 30 days, 20% of GFP+ generated from these progenitors differentiate into GFAP+ astrocytes. Unilateral intrahippocampal administration of the chemoconvulsants kainic acid (KA) or pilocarpine (PL) triggered epileptiform discharges and led to a significant increase in the number of GFP+ cells in both ipsi and contralateral DG. However, while PL favored the differentiation of neurons in both ipsi- and contralateral sides, KA stimulated neurogenesis only in the contralateral side. In the ipsilateral side, KA injection led to an unexpected increase of astrogliogenesis in the Dcx-lineage. We also observed a small number of GFP+/GFAP+ cells displaying radial-glia morphology ipsilaterally 3 days after KA administration, suggesting that some Dcx-progenitors could regress to a multipotent stage. The boosted neurogenesis and astrogliogenesis observed in the Dcx-lineage following chemoconvulsants administration correlated, respectively, with preservation or degeneration of the parvalbuminergic plexus in the DG. Increased inflammatory response, by contrast, was observed both in the DG showing increased neurogenesis or astrogliogenesis. Altogether, our data support the view that cell lineage progression in the adult hippocampus is not unidirectional and could be modulated by local network activity and GABA-mediated signaling.

Highlights

Generation and functional integration of new neurons occurs at discrete sites of the adult central nervous system
Three days after TAM administration, 97% of GFP+ cells in the dentate gyrus (DG) co-expressed the protein DCX and were either cells with short horizontal processes located in the subgranular zone (SGZ) or cells with radially oriented processes located in the inner half of the granular layer (Figures 1B–D,K; n = 5 animals; 106 GFP+/DCX+ out of 108 GFP+ cells), as expected for type 2 progenitors and immature neurons, respectively (Brown et al, 2003; Jagasia et al, 2009)
Comprehensive knowledge about the intermediate steps enacted in the transition from an adult neural stem cell to a mature neuronal state is critical to understand how neurons can be generated in the adult central nervous system

Summary

Introduction

Generation and functional integration of new neurons occurs at discrete sites of the adult central nervous system (for review, see Lledo et al, 2006). It is largely believed that RGCs progress either through an astroglial-lineage producing new RGCs and astrocytes or a neuronal-lineage, comprising intermediate/type 2b and 3 progenitors, which terminates with the generation of new granule neurons (Steiner et al, 2004; Suh et al, 2007; Bonaguidi et al, 2011; Encinas et al, 2011; Dumitru et al, 2017) These intermediate progenitors can be genetically manipulated to generate glial cells (Braun et al, 2015), it remains unknown whether cell-extrinsic signals could modulate their gliogenic potential

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