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Proliferating reactive astrocytes are regulated by Notch-1 in the peri-infarct area after stroke.

ABSTRACT: The formation of reactive astrocytes is common after central nervous system injuries such as stroke. However, the signaling pathway(s) that control astrocyte formation and functions are poorly defined. We assess the effects of Notch 1 signaling in peri-infarct-reactive astrocytes after stroke.We examined reactive astrocyte formation in the peri-infarct area 3 days after distal middle cerebral artery occlusion with or without ?-secretase inhibitor treatment. To directly study the effects of inhibiting a ?-secretase cleavage target in reactive astrocytes, we generated glial fibrillary acidic protein-CreER™:Notch 1 conditional knockout mice.Gamma-secretase inhibitor treatment after stroke decreased the number of proliferative glial fibrillary acidic protein-positive reactive astrocytes and RC2-positive reactive astrocytes directly adjacent to the infarct core. The decrease in reactive astrocytes correlated with an increased number of CD45-positive cells that invaded into the peri-infarct area. To study the influence of reactive astrocytes on immune cell invasion, ex vivo immune cell invasion assays were performed. We found that a ?-secretase-mediated pathway in astrocytes affected Jurkat cell invasion. After tamoxifen treatment, glial fibrillary acidic protein-CreER™:Notch 1 conditional knockout mice had a significantly decreased number of proliferating reactive astrocytes and RC2-positive reactive astrocytes. Tamoxifen treatment also led to an increased number of CD45-positive cells that invaded the peri-infarct area.Our results demonstrate that proliferating and RC2-positive reactive astrocytes are regulated by Notch 1 signal transduction and control immune cell invasion after stroke.

SUBMITTER: Shimada IS

PROVIDER: S-EPMC4469355 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Proliferating reactive astrocytes are regulated by Notch-1 in the peri-infarct area after stroke.

Shimada Issei S IS Borders Alyssa A Aronshtam Alexander A Spees Jeffrey L JL

Stroke 20110811 11

<h4>Background and purpose</h4>The formation of reactive astrocytes is common after central nervous system injuries such as stroke. However, the signaling pathway(s) that control astrocyte formation and functions are poorly defined. We assess the effects of Notch 1 signaling in peri-infarct-reactive astrocytes after stroke.<h4>Methods</h4>We examined reactive astrocyte formation in the peri-infarct area 3 days after distal middle cerebral artery occlusion with or without γ-secretase inhibitor tr ...[more]

PMID: 21836083

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Project description:BackgroundAltered neuronal connectivity in peri-infarct tissue is an important contributor to both the spontaneous recovery of neurological function that commonly develops after stroke and improvements in recovery that have been induced by experimental treatments in animal models. Microglia and astrocytes are primary determinants of the environment in peri-infarct tissue and hence strongly influence the potential for neuronal plasticity. However, the specific roles of these cells and the timing of critical changes in their function are not well understood. Minocycline can protect against ischemic damage and promote recovery. These effects are usually attributed, at least partially, to the ability of this drug to suppress microglial activation. This study tested the ability of minocycline treatment early after stroke to modify reactive responses in microglia and astrocytes and improve recovery.MethodsStroke was induced by photothrombosis in the forelimb sensorimotor cortex of Sprague-Dawley rats. Minocycline was administered for 2 days after stroke induction and the effects on forelimb function assessed up to 28 days. The responses of peri-infarct Iba1-positive cells and astrocytes were evaluated using immunohistochemistry and Western blots.ResultsInitial characterization showed that the numbers of Iba1-positive microglia and macrophages decreased in peri-infarct tissue at 24 h then increased markedly over the next few days. Morphological changes characteristic of activation were readily apparent by 3 h and increased by 24 h. Minocycline treatment improved the rate of recovery of motor function as measured by a forelimb placing test but did not alter infarct volume. At 3 days, there were only minor effects on core features of peri-infarct microglial reactivity including the morphological changes and increased density of Iba1-positive cells. The treatment caused a decrease of 57% in the small subpopulation of cells that expressed CD68, a marker of phagocytosis. At 7 days, the expression of glial fibrillary acidic protein and vimentin was markedly increased by minocycline treatment, indicating enhanced reactive astrogliosis.ConclusionsEarly post-stroke treatment with minocycline improved recovery but had little effect on key features of microglial activation. Both the decrease in CD68-positive cells and the increased activation of astrogliosis could influence neuronal plasticity and contribute to the improved recovery.

Project description:BackgroundFollowing stroke, changes in neuronal connectivity in tissue surrounding the infarct play an important role in both spontaneous recovery of neurological function and in treatment-induced improvements in function. Microglia and astrocytes influence this process through direct interactions with the neurons and as major determinants of the local tissue environment. Subpopulations of peri-infarct glia proliferate early after stroke providing a possible target to modify recovery. Treatment with cell cycle inhibitors can reduce infarct volume and improve functional recovery. However, it is not known whether these inhibitors can influence neurological function or alter the responses of peri-infarct glia without reducing infarction. The present study aimed to address these issues by testing the effects of the cell cycle inhibitor, olomoucine, on recovery and peri-infarct changes following photothrombotic stroke.MethodsStroke was induced by photothrombosis in the forelimb sensorimotor cortex in Sprague-Dawley rats. Olomoucine was administered at 1 h and 24 h after stroke induction. Forelimb function was monitored up to 29 days. The effects of olomoucine on glial cell responses in peri-infarct tissue were evaluated using immunohistochemistry and Western blotting.ResultsOlomoucine treatment did not significantly affect maximal infarct volume. Recovery of the affected forelimb on a placing test was impaired in olomoucine-treated rats, whereas recovery in a skilled reaching test was substantially improved. Olomoucine treatment produced small changes in aspects of Iba1 immunolabelling and in the number of CD68-positive cells in cerebral cortex but did not selectively modify responses in peri-infarct tissue. The content of the astrocytic protein, vimentin, was reduced by 30% in the region of the lesion in olomoucine-treated rats.ConclusionsOlomoucine treatment modified functional recovery in the absence of significant changes in infarct volume. The effects on recovery were markedly test dependent, adding to evidence that skilled tasks requiring specific training and general measures of motor function can be differentially modified by some interventions. The altered recovery was not associated with specific changes in key responses of peri-infarct microglia, even though these cells were considered a likely target for early olomoucine treatment. Changes detected in peri-infarct reactive astrogliosis could contribute to the altered patterns of functional recovery.

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Proliferating reactive astrocytes are regulated by Notch-1 in the peri-infarct area after stroke.

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Proliferating reactive astrocytes are regulated by Notch-1 in the peri-infarct area after stroke.

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