RESPONSE OF STRIATAL ASTROCYTES TO NEURONAL DEAFFERENTATION - AN IMMUNOCYTOCHEMICAL AND ULTRASTRUCTURAL-STUDY

This ultrastructural and light microscopic immunocytochemical study de scribes the time course of anatomical changes that occur in striatal a strocytes in response to neuronal deafferentation in young adult rats and the coordinate distribution of two astrocytic proteins involved in reactive synaptogenesis, glial fibrillary acidic protein and clusteri n. We found that following a unilateral lesion of the cerebral cortex, striatal astrocytes undergo a rapid ultrastructural transformation fr om a protoplasmic to a reactive type of astroglia and are the primary cells involved in the removal of degenerating axon terminals, but not axons of passage, from the neuropil. In addition, at 10 and 27 days po stlesion, processes of reactive astrocytes are also seen to occupy vac ant postsynaptic spines after degenerating presynaptic terminals are r emoved, suggesting that they may also participate in the reinnervation of the deafferented neurons. By immunocytochemistry, reactive astrocy tes were characterized by a significant increase in the intensity of g lial fibrillary acidic protein staining beginning at three days postle sion and lasting for at least 27 days postlesion. Reactive astrocytes were characterized by cellular hypertrophy and an increase in the dens ity of immunoreactive processes distributed throughout the deafferente d striatum. However, our analysis of astrocyte cell number found no ev idence of astrocyte proliferation in response to the deafferentation l esion. Although previous in situ hybridization studies have reported e levated clusterin messenger RNA in reactive astrocytes after decortica tion, clusterin immunoreactivity was not seen in the cell soma of reac tive astrocytes but was distributed as punctate deposits, ranging from 1 to 2 mu m in diameter, within the neuropil of the deafferented stri atum. At 10 days postlesion, the distribution of clusterin staining ap peared as large aggregates of immunoreactive deposits adjacent to neur ons. However, by 27 days postlesion, the aggregates of clusterin react ion product were replaced by a fine scattering of individual punctate deposits distributed evenly over the dorsal part of the deafferented s triatum. These data support the notion that reactive astrocytes serve multiple, time-dependent roles in response to brain injury and are inv olved in both the removal of degenerative debris from the lesion site as well as in reforming the synaptic circuitry of the damaged brain. O ur data suggest that, in response to decortication, reactive astrocyte s are the primary cells responsible for removing degenerating axon ter minals, but not axons of passage, from the deafferented striatum and t hat the coordinate increase in glial fibrillary acidic protein may ser ve to stabilize the extension of reactive astrocytic processes during phagocytosis. By comparison, clusterin is most likely an extracellular protein released by reactive astrocytes in response to brain damage. Possible roles for clusterin in reactive synaptogenesis include servin g as a lipoprotein to facilitate the distribution of recycled lipid to actively sprouting axons and dendrites or regulation of complement-me diated responses.