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.
Bush
T G
TG
Medical Research Council Cambridge Centre for Brain Repair, and Department of Anatomy, University of Cambridge, United Kingdom.
Puvanachandra
N
N
Horner
C H
CH
Polito
A
A
Ostenfeld
T
T
Svendsen
C N
CN
Mucke
L
L
Johnson
M H
MH
Sofroniew
M V
MV
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