GENETIC INFLUENCES ON CELLULAR REACTIONS TO BRAIN INJURY - ACTIVATIONOF MICROGLIA IN DENERVATED NEUROPIL IN MICE CARRYING A MUTATION (WLD(S)) THAT CAUSES DELAYED WALLERIAN DEGENERATION

This study examines the relationship between the appearance of degener ative changes in synaptic terminals and axons and the activation of mi croglia in denervated neuropil regions of normal mice of the C57BL/6 s train and mutant mice (Wld(S)), in which Wallerian degeneration is sub stantially delayed. The time course of degenerative changes in synapti c terminals and axons was assessed using selective silver staining. Mi croglial cells were identified by immunostaining for Mac-1, a monoclon al antibody to the CR3 complement receptor, and by histochemical stain ing for nucleoside diphosphatase (NDPase). Increased argyrophilia, ind icative of degenerative changes, was evident as early as 1 day populat ion in normal mice, but was not seen until 6-8 days in mice with the W ld(S) mutation. Microglial activation in normal C57BL/6 mice was evide nt by 24 hours postlesion, as evidenced by increased immunostaining fo r Mac-1, increased histochemical staining for NDPase, and morphologica l changes indicative of an activated phenotype (short, thick processes ). Quantitative evaluation of immunostaining for Mac-1 revealed that p eak activation occurred between 2 and 6 days postlesion with a return to a quiescent phenotype by 12 days. In contrast, the microglial respo nse was significantly delayed and prolonged in mice bearing the Wld(S) mutation. Activated microglia were not seen within the deafferented a rea until 6 to 8 days postlesion and peak activation occurred between 12 and 20 days postlesion. These data suggest that the response of mic roglia in denervated neuropil zones is triggered by the same types of degenerative changes that cause increased argyrophilia as detected by selective silver staining methods. (C) 1997 Wiley-Liss, Inc.