The use of transgenic mouse models to study the roles of astrocytes after traumatic brain injury.

摘要

Astrocytes are the most numerous cell type in the central nervous system (CNS) and maintain many homeostatic mechanisms. Following CNS injury, astrocytes respond by hypertrophy, increased gene expression and cellular proliferation, a process termed 'reactive astrocytosis' that may contribute to neuroprotection and neurotoxicity. Their roles are not well understood.; To examine cellular responses to injury we used transgenic mouse models to manipulate the astrocyte response. To model human traumatic brain injury (TBI) we used the controlled cortical impact (CCI) model to produce different injury severities. Following an analysis of tissue morphology, immunohistochemistry, cortical volume and behavioral testing, we report on the effects of (1) the presence of reactive astrocytes, (2) the absence of dividing, reactive astrocytes and (3) deletion of a gene thought to modulate reactive astrocytosis after CNS injury.; In GFAP-TK (glial fibrillary acidic protein-thymidine kinase) transgenic mice, than anti-viral agent ganciclovir selectively ablates dividing, reactive astrocytes after injury. After moderate CCI, ablation resulted in (1) a significant 45% loss of injured cortical tissue volume at 7d that increased to 60% by 28d, (2) increased neuronal death, and (3) a highly upregulated inflammatory response, and therefore ablation exacerbated the injury compared to control mice. Due to the magnitude of tissue loss after severe CCI, cortical volumes were not statistically different between nontransgenic and transgenic mice.; In GFAP-STAT3-CKO (signal transducer and activator of transcription-conditional knock-out) transgenic mice, Cre-loxP technology was used to selectively delete STAT3 from astrocytes to examine its role in reactive astrocytosis. Our findings show (1) STAT3 is required for basal GFAP expression levels in gray but not white matter astrocytes and (2) STAT3 deletion attenuated reactive astrocytosis in gray but not white matter astrocytes after moderate CCI, suggesting GFAP regulation may involve different signaling pathways in the two astrocyte subtypes; (3) cortical volumes were not statistically difference after moderate CCI compared to control mice.; We have further defined astrocyte cell biology following CNS injury, specifically the effects of astrocyte reactivity on neighboring cell types, and regulation of a signaling pathway leading to reactive astrocytosis. These findings may be relevant in developing successful therapeutic strategies following human TBI.