Abstract
BackgroundAstroglial cells are activated following injury and up-regulate the expression of the intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin. Adult mice lacking the intermediate filament proteins GFAP and vimentin (GFAP−/−Vim−/−) show attenuated reactive gliosis, reduced glial scar formation and improved regeneration of neuronal synapses after neurotrauma. GFAP−/−Vim−/− mice exhibit larger brain infarcts after middle cerebral artery occlusion suggesting protective role of reactive gliosis after adult focal brain ischemia. However, the role of astrocyte activation and reactive gliosis in the injured developing brain is unknown.Methodology/Principal FindingsWe subjected GFAP−/−Vim−/− and wild-type mice to unilateral hypoxia-ischemia (HI) at postnatal day 9 (P9). Bromodeoxyuridine (BrdU; 25 mg/kg) was injected intraperitoneally twice daily from P9 to P12. On P12 and P31, the animals were perfused intracardially. Immunohistochemistry with MAP-2, BrdU, NeuN, and S100 antibodies was performed on coronal sections. We found no difference in the hemisphere or infarct volume between GFAP−/−Vim−/− and wild-type mice at P12 and P31, i.e. 3 and 22 days after HI. At P31, the number of NeuN+ neurons in the ischemic and contralateral hemisphere was comparable between GFAP−/−Vim−/− and wild-type mice. In wild-type mice, the number of S100+ astrocytes was lower in the ipsilateral compared to contralateral hemisphere (65.0±50.1 vs. 85.6±34.0, p<0.05). In the GFAP−/−Vim−/− mice, the number of S100+ astrocytes did not differ between the ischemic and contralateral hemisphere at P31. At P31, GFAP−/−Vim−/− mice showed an increase in NeuN+BrdU+ (surviving newly born) neurons in the ischemic cortex compared to wild-type mice (6.7±7.7; n = 29 versus 2.9±3.6; n = 28, respectively, p<0.05), but a comparable number of S100+BrdU+ (surviving newly born) astrocytes.Conclusions/SignificanceOur results suggest that attenuation of reactive gliosis in the developing brain does not affect the hemisphere or infarct volume after HI, but increases the number of surviving newborn neurons.
Highlights
The central nervous system (CNS) contains abundance of astroglial cells which induce formation of neuronal synapses and support neurons structurally and metabolically [1]
There was no difference in the volume of the ipsilateral hemisphere (38.9610.3 mm3, n = 26 vs. 35.5611.7 mm3, n = 27) or the contralateral hemisphere (46.068.5 mm3 vs. 44.267.1 mm3) between GFAP2/2Vim2/2 and wild-type mice at P31, i.e. 22 days after HI (Fig. 2a)
Astrocytes respond to hypoxia-ischemia (HI) by morphological and functional changes as early as 8 hours after the insult and have been implicated to play a role in the pathophysiological events that lead to the brain damage after HI [15,16]
Summary
The central nervous system (CNS) contains abundance of astroglial cells which induce formation of neuronal synapses and support neurons structurally and metabolically [1]. One of the hallmarks of astrocyte activation and the resulting reactive gliosis is the upregulation of the intermediate filament (IF) system (known as nanofilament system) composed of glial fibrillary acidic protein (GFAP), vimentin, nestin and synemin [2,3]. Neuroprotection by reactive astrocytes through up-regulation of glutathione was demonstrated following oxidative stress [4,5]. Astroglial cells are activated following injury and up-regulate the expression of the intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin. Adult mice lacking the intermediate filament proteins GFAP and vimentin (GFAP2/2Vim2/2) show attenuated reactive gliosis, reduced glial scar formation and improved regeneration of neuronal synapses after neurotrauma. GFAP2/2Vim2/2 mice exhibit larger brain infarcts after middle cerebral artery occlusion suggesting protective role of reactive gliosis after adult focal brain ischemia. The role of astrocyte activation and reactive gliosis in the injured developing brain is unknown
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