Inhibition of collagen IV deposition promotes regeneration of injured CNS axons.
Scarring impedes axon regrowth across the lesion site and is one major extrinsic constraint to effective regeneration in the adult mammalian central nervous system. In the present study we determined whether specific biochemical or immunochemical modulation of one major component of the scar, the basal membrane (BM), would provide a means to stimulate axon regeneration in the mechanically transected postcommissural fornix of the adult rat. Basal membrane developed within the first 2 weeks after transection in spatiotemporal coincidence with the abrupt growth arrest of spontaneously regrowing axons. Local injection of anticollagen IV antibodies or alpha, alpha'-dipyridyl, an inhibitor of collagen triple helix formation and synthesis, significantly reduced lesion-induced BM deposition. This treatment allowed massive axon elongation across the lesion site. Anterograde tracing provided unequivocal evidence that regenerating axons follow their original pathway, reinnervate the appropriate target, the mammillary body, and become remyelinated with compact myelin. Presynaptic electrophysiological recordings of regenerated fibre tracts showed recovery to nearly normal conduction properties. Our results indicate that lesion-induced BM is an impediment for successful axonal regeneration and its reduction is a prerequisite and sufficient condition for regrowing axons to cross the lesion site.
Stichel
C C
CC
Department of Neurology, Heinrich-Heine-University Düsseldorf, Germany.
Hermanns
S
S
Luhmann
H J
HJ
Lausberg
F
F
Niermann
H
H
D'Urso
D
D
Servos
G
G
Hartwig
H G
HG
Müller
H W
HW
D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001369:Axons / Q000737:chemistry / Q000502:physiology*; D002462:Cell Membrane / Q000737:chemistry / Q000502:physiology; D003094:Collagen / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D003714:Denervation; D004594:Electrophysiology; D005260:Female; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology / Q000293:injuries*; D007202:Indicators and Reagents / Q000494:pharmacology; D008297:Male; D008326:Mammillary Bodies / Q000166:cytology / Q000293:injuries; D008854:Microscopy, Electron; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology
D000906:Antibodies; D007202:Indicators and Reagents; D013779:Tetrodotoxin; D015082:2,2'-Dipyridyl; D003094:Collagen