Degeneration and proliferation of astrocytes in the mouse dentate gyrus after pilocarpine-induced status epilepticus

Abstract

Astrocytes are relatively resistant to injury compared to neurons and oligodendrocytes. Here, we report transient region-specific loss of astrocytes in mice early after pilocarpine-induced status epilepticus (SE). In the dentate hilus, immunoreactivity for glial acidic fibrillary protein (GFAP) was decreased, and the number of healthy appearing GFAP-or S100β-positive cells was significantly reduced (≥ 65%) 1 and 3 days after pilocarpine-induced SE. Many remaining GFAPpositive cells were shrunken, and 1 day after SE electron microscopy revealed numerous electrondense degenerating astrocyte processes and degenerating glial somata in the hilus. Degeneration of GFAP-expressing cells may be linked to hilar neuronal death, because we did not observe loss of astrocytes after kainate-induced SE, after which hilar neurons remained intact. Ten days after SE, hilar GFAP immunoreactivity had returned, partially from GFAP-positive cells in the hilus. Unlike control mice, many GFAP-positive hilar processes originated from cell bodies located in the subgranular zone (SGZ). To investigate whether proliferation contributes to hilar repopulation, we injected 5-bromo-2′-deoxyuridine (BrdU) 3 days after SE. Five hours later and up to 31 days after SE, many BrdU/GFAP colabeled cells were found in the hilus and the SGZ, some with hilar processes, indicating that proliferation in both areas contributes to generation of hilar astrocytes and astrocyte processes. In contrast to pilocarpine-induced SE in mice, astrocyte degeneration was not found after pilocarpine-induced SE in rats. These findings demonstrate astrocyte degeneration in the mouse dentate hilus specifically in the mouse pilocarpine epilepsy model, followed by astrogenesis leading to hilar repopulation.

Spatiotemporal characteristics of astroglial death in the rat hippocampo‐entorhinal complex following pilocarpine‐induced status epilepticus

“…These discrepancies may be due to the species-specific susceptibility of astroglia to pilocarpineinduced SE or the difference of neuroanatomical characteristics between rats and mice. Indeed, Borges et al (2006) also reported that astroglial degeneration was not observed in the rat hilus following pilocarpine-induced SE, unlike mouse. Further studies are needed to determine whether astroglial degeneration is differentially expressed in astroglial types located in different regions of the rodent hippocampal complex.…”

“…Therefore, our findings underline the possibility that astroglial loss may play a potential role in epileptogenesis. Borges et al (2006) reported that pilocarpine-induced SE evoked loss of GFAP labeling in the mouse hilus, not in the molecular layer. Therefore, they suggested that the mouse hilar astroglia might be vulnerable to pilocarpine-SE or local neurodegeneration of the hilus.…”

Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus

“…SE-induced reactive astrogliosis plays a significant role in the aberrant synaptic remodeling of the hippocampus thought to underlie the development of epilepsy (Jorgensen et al, 1993;Niquet et al, 1994aNiquet et al, , 1994bRepresa et al, 1995). Reactive astrocytes that proliferate in response to seizures express several genes that promote neurite outgrowth (Represa et al, 1993;Niquet et al, 1994aNiquet et al, , 1994bStringer, 1996) and the increase in the expression of these genes coincides with both the emergence of mossy fiber sprouting and the period when both GFAP and hippocampal cell proliferation are elevated (Khrestchatisky et al, 1995;Represa et al, 1995;Bengzon et al, 1997;Parent et al, 1997;Borges et al, 2006). An attenuation of seizure-induced astrogliosis in SUP rats may thus indicate a reduced progression of epilepsy following SE.…”

The adenosine kinase hypothesis of epileptogenesis

“…This is also true for newer antiepileptic drugs, such as gabapentin and pregabalin, which have recently been demonstrated to act on the α 2 -δ subunit of a voltagegated calcium channel, thus attenuating the calcium flux into neurons (Davies et al, 2007;Field et al, 2007;Taylor et al, 2007). Apart from dysfunction of neuronal networks (Holmes and Ben-Ari, 2003), dysfunction of astrocytes has recently emerged as a critical component of epileptogenesis adding an additional layer of complexity to the underlying disease process (Borges et al, 2006;Tian et al, 2005).…”