Brain Advance Access originally published online on July 5, 2006
Brain 2006 129(10):2761-2772; doi:10.1093/brain/awl165
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Essential protective roles of reactive astrocytes in traumatic brain injury
Departments of Neurobiology, University of California Los Angeles, CA, USA Neurosurgery, University of California Los Angeles, CA, USA
Correspondence to: Michael V. Sofroniew, Department of Neurobiology, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1763, USA E-mail: sofroniew{at}mednet.ucla.edu
Astrocytes respond to traumatic brain injury (TBI) by altered gene expression, hypertrophy and proliferation that occur in a gradated fashion in relation to the severity of the injury. Both beneficial and detrimental effects have been attributed to reactive astrocytes, but their roles after brain injury are not well understood. To investigate these roles, we determined the effects on cortical tissue of ablating reactive astrocytes after contusion injury generated by controlled cortical impact (CCI) of different severities in transgenic mice that express a glial fibrillary acidic protein–herpes simplex virus–thymidine kinase transgene. Treatment of these mice with the antiviral agent, ganciclovir, conditionally ablates proliferating reactive astrocytes. Moderate or severe CCI were generated with a precisely regulated pneumatic piston, and forebrain tissue was evaluated using immunohistochemistry and quantitative morphometry. Moderate CCI in control mice triggered extensive and persisting reactive astrogliosis, with most neurons being preserved, little inflammation and an 18% loss of cortical tissue beneath the impact site. Ablation of reactive astrocytes after moderate CCI in transgenic mice caused substantial neuronal degeneration and inflammation, with a significantly greater 60% loss of cortical tissue. Severe CCI in control mice caused pronounced neuronal degeneration and loss of about 88% of cortical tissue that was not significantly altered by ablating reactive astrocytes in transgenic mice. Thus, ablation of dividing reactive astrocytes exacerbated cortical degeneration after moderate CCI, but did not alter cortical degeneration after severe CCI. These findings indicate that the reactive astrocytes play essential roles in preserving neural tissue and restricting inflammation after moderate focal brain injury.
Key Words: reactive astrocytes; traumatic brain injury; inflammation; transgenic mice; neural degeneration; glial fibrillary acidic protein; contusion; controlled cortical impact
Abbreviations: CCI, controlled cortical impact; TBI, traumatic brain injury
Received February 23, 2006. Revised April 24, 2006. Accepted June 25, 2006.
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