Seizures preferentially stimulate proliferation of radial glia‐like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis

Abstract

Kainate-induced seizures increase hippocampal neurogenesis. Glial fibrillary acidic protein-positive astrocytes with radial processes in the dentate gyrus share many of the characteristics of radial glia and appear to act as precursor cells for adult dentate neurogenesis. Using the chemoconvulsant kainate and transgenic mice with human glial-fibrillary acidic protein (hGFAP) promoter-controlled enhanced green fluorescent protein (EGFP) expression, we examined the proliferation, morphology and electrophysiological properties of astrocytes in the neurogenic subgranular zone of the dentate gyrus in control animals and upon the induction of seizure-induced cell proliferation, three days post-kainate. EGFP-positive cells with and without radial processes could easily be distinguished. Kainate treatment caused a significant increase in the total number of proliferating EGFP-positive cells, particularly a tenfold elevation in the number of proliferating radial glia-like astrocytes, and also caused a preferential shift in the dividing cell population towards cells expressing EGFP. Immunohistochemical analysis revealed a surprisingly low proportion of cells coexpressing the astroglial marker S100beta and EGFP. Kainate increased the number of EGFP-positive, S100beta-positive and S100beta-positive-EGFP-positive astrocytes in the subgranular zone. We also report a subset of faintly EGFP-positive cells expressing markers of early neuronal differentiation. Patch-clamp analysis revealed the presence of three functionally different populations of EGFP-positive cells in both kainate and control tissue. We conclude that there is an early increase in proliferating radial glia-like astrocytes in the dentate after kainate-induced seizures, consistent with a recruitment of precursors for seizure-induced neurogenesis.

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

“…Additionally, a recent report from Varodayan et al [48] demonstrated that seizure leads to a shortening of the cell cycle in DG precursors, suggesting a link between G 1 phase length and seizureinduced proliferation. To address whether Cdk6 plays a role during seizure-induced proliferation, we injected kainic acid (KA) to WT and Cdk6 À/À animals and quantified precursor cell proliferation in the DG 72 hours later, with a protocol that was described previously [49,50]. Of note, we consistently observed a large overlap between Cdk4/6 and Ki-67 expression 72 hours after either NaCl or KA administration (Supporting Information Fig.…”

“…7A-7E). Because seizure has been demonstrated to initially trigger the proliferation of immature/noncommitted precursors [49,50], we then quantified the numbers of GFAP þ /Ki-67 þ and Sox2 þ /Ki-67 þ cells following KA injection. We observed a dramatic increase of the number of GFAP þ and Sox2 þ proliferating precursors, independently of the mouse genotype (Fig.…”

Connexin expression by radial glia-like cells is required for neurogenesis in the adult dentate gyrus

“…How these proliferating RG-like cells are integrated into the hippocampal network is poorly understood. Epileptic seizures or ischemic insults can trigger proliferation of RG-like cells, while the transit-amplifying progenitors in the DG are less affected (3,5). However, RG-like precursor cells neither receive functional GABAergic nor glutamatergic synaptic input (6,7).…”

“…In the subgranular zone (SGZ) of the dentate gyrus (DG), astrocytes with a radial glia (RG)-like morphology are considered stem cells (1). They extend a long branching process through the granule cell layer (GCL), electrophysiologically display a passive current pattern (2)(3)(4), and express GFAP and nestin. How these proliferating RG-like cells are integrated into the hippocampal network is poorly understood.…”

Plasticity of neuropeptide Y in the dentate gyrus after seizures, and its relevance to seizure-induced neurogenesis

“…In addition, these precursors may develop into non-neuronal cells. Indeed, their development may arise entirely from radial glia, dividing into one or more daughter cells that become neurons, as well as additional cells that ultimately become mature astrocytes [20,21].…”