Delayed macrophage responses and myelin clearance during Wallerian degeneration in the central nervous system: the dorsal radiculotomy model.

All aspects of Wallerian degeneration (WD)--axonal breakdown, glial and macrophage responses, and clearance of myelin debris--have generally been considered to occur more slowly in the central nervous system (CNS) than in the peripheral nervous system (PNS). We reevaluated this issue by comparing the temporal pattern of Wallerian degeneration in nerve fibers with segments extending through both the PNS and the CNS. The L4, L5, and L6 dorsal roots in the rat were transected, and WD in the dorsal roots and the dorsal columns was compared at intervals up to 8 months, using electron microscopy and immunostaining to identify and characterize the different cell types. The initial breakdown of axoplasm was complete by 72 h both in the PNS and in the CNS portions of these axons. All other aspects of WD were strikingly delayed in the CNS when compared to those in the PNS. Macrophages (from the circulation) increased in number (Days 2-4 after axotomy) in the root. In contrast, although there was an early and transient period (peaking at Day 3) of microglial activation in the degenerating dorsal column, the appearance of round macrophages was delayed until Days 18-21. Both axonal debris and myelin debris were almost completely cleared by 30 days in the PNS, but remained over 90 days in the CNS. Axonal regeneration was vigorous in the dorsal root but these sprouts did not invade the dorsal columns. The dorsal root entry zone provided a sharp anatomic demarcation between the PNS and CNS patterns of Wallerian degeneration. These results suggest that circulating macrophages have ready access to degenerating peripheral nerves, but are largely or completely excluded from degenerating CNS tracts, so that the macrophages (that ultimately appear) originate primarily from the stellate microglia.