Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice.
Reactive astrocytes adjacent to a forebrain stab injury were selectively ablated in adult mice expressing HSV-TK from the Gfap promoter by treatment with ganciclovir. Injured tissue that was depleted of GFAP-positive astrocytes exhibited (1) a prolonged 25-fold increase in infiltration of CD45-positive leukocytes, including ultrastructurally identified monocytes, macrophages, neutrophils, and lymphocytes, (2) failure of blood-brain barrier (BBB) repair, (3) substantial neuronal degeneration that could be attenuated by chronic glutamate receptor blockade, and (4) a pronounced increase in local neurite outgrowth. These findings show that genetic targeting can be used to ablate scar-forming astrocytes and demonstrate roles for astrocytes in regulating leukocyte trafficking, repairing the BBB, protecting neurons, and restricting nerve fiber growth after injury in the adult central nervous system.
Medical Research Council Cambridge Centre for Brain Repair, and Department of Anatomy, University of Cambridge, United Kingdom.
T G
TG
Bush
N
N
Puvanachandra
C H
CH
Horner
A
A
Polito
T
T
Ostenfeld
C N
CN
Svendsen
L
L
Mucke
M H
MH
Johnson
M V
MV
Sofroniew
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001812:Blood-Brain Barrier; D001930:Brain Injuries / Q000473:pathology*; D002452:Cell Count; D002465:Cell Movement; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D006624:Hippocampus / Q000473:pathology; D006651:Histocytochemistry; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000473:pathology*; D016501:Neurites / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D014951:Wounds, Stab / Q000473:pathology*
D005904:Glial Fibrillary Acidic Protein; D013937:Thymidine Kinase; D015774:Ganciclovir