Inhibition of collagen synthesis overrides the age-related failure of regeneration of nigrostriatal dopaminergic axons

Abstract

To investigate the mechanism of the age-related failure of regeneration of transected axons, nigrostriatal dopaminergic axons were unilaterally transected in the lateral hypothalamus in adult mice and in immature mice aged postnatal days 7, 14, and 21. Ten days after the transection, tyrosine hydroxylase-immunoreactive axons had regenerated from caudally to rostrally across the lesion site in mice transected at postnatal day 7, whereas they stopped and did not extend across the lesion site in mice transected at postnatal day 14 or older. Reactive astrocytes bearing chondroitin sulfate proteoglycans were observed around the lesion in mice transected at all ages. However, a fibrotic scar containing type IV collagen-immunoreactive deposits, which was consistently formed at the lesion site in mice transected at postnatal day 14 or older, was not formed in mice lesioned at postnatal day 7. When 2,2'-dipyridyl, an inhibitor of collagen synthesis, was injected into the lesion site at the time of transection in both postnatal day 14 and adult mice, the deposition of type IV collagen and the formation of a fibrotic scar were completely prevented, and large numbers of tyrosine hydroxylase-immunoreactive axons extended across the lesion and reinnervated the striatum. These results imply that the fibrotic scar formed in the lesion site is a crucial impediment to the regeneration of ascending dopaminergic axons in adult mice and suggest that type IV collagen is required for the development of the fibrotic response to adult brain injury.