This study compares the reactive changes in astrocytes in denervated neuropil regions in normal mice and in mice carrying the Wld(S) mutation which leads to delayed Wallerian degeneration. In situ hybridization and immunocytochemical techniques were used to define the time course of changes in the levels of glial fibrillary acidic protein (GFAP) and GFAP mRNA in the denervated neuropil of the hippocampus after unilateral aspiration lesions of the entorhinal cortex. In control mice, GFAP mRNA levels increased rapidly in the denervated neuropil to a peak that was about tenfold higher than control at 2-4 days, decreased between 6 and 8 days postlesion, and then increased again to a second peak at 10 days postlesion. Increases in immunostaining for GFAP were evident by 2 days, remained elevated until 12 days postlesion and then decreased slowly. In mice carrying the Wld(S) mutation, the upregulation of GFAP mRNA levels in the denervated laminae was substantially delayed. Strikingly absent was the dramatic increase in labeling at 2-4 days postlesion which was such a prominent feature of the response in control animals. Peak labeling in the denervated laminae was not seen until 10-12 days postlesion. The development of a well-defined band of intensely immunostained and hypertrophied astrocytes in the denervated zone was also delayed in the Wld(S) animals, although there were modest increases in immunostaining as early as 2 days postlesion that were seen throughout the hippocampus ipsilateral to the lesion. These results suggest that degenerative changes in axons and synaptic terminals are the principal trigger for upregulating GFAP expression in the denervated neuropil, although other signals also play a role in the early postlesion response.