Robust regeneration of CNS axons through a track depleted of CNS glia

Transected CNS axons do not regenerate spontaneously but may do so if given an appropriate environment through which to grow. Since molecules associat ed with CNS macroglia are thought to be inhibitory to axon regeneration, we have tested the hypothesis that removing these cell types from an area of brain will leave an environment more permissive for axon regeneration. Adul t rats received unilateral knife cuts of the nigrostriatal tract and ethidi um bromide (EB) was used to create a lesion devoid of astrocytes, oligodend rocytes, intact myelin sheaths, and NG2 immunoreactive cells from the site of the knife cut to the ipsilateral striatum (a distance of 6 mm), The rege nerative response and the EB lesion environment was examined with immunosta ining and electron microscopy at different timepoints following surgery. We report that large numbers of dopaminergic nigral axons regenerated for ove r 4 mm through EB lesions. At 4 days postlesion dopaminergic sprouting was maximal and the axon growth front had reached the striatum, but there was n o additional growth into the striatum after 7 days. Regenerating axons did not leave the EB lesion to form terminals in the striatum, there was no rec overy of function, and the end of axon growth correlated with increasing gl ial immunoreactivity around the EB lesion. We conclude that the removal of CNS glia promotes robust axon regeneration but that this becomes limited by the reappearance of nonpermissive CNS glia. These results suggest, first, that control of the glial reaction is likely to be an important feature in brain repair and, second, that reports of axon regeneration must be interpr eted with caution since extensive regeneration can occur simply as a result of a major glia-depleting lesion, rather than as the result of some other specific intervention. (C) 2000 Academic Press.