Acta Neuropathol (2010) 119:7–35 15 necrosis, infection or autoimmune-triggered inﬂammatory inﬁltration (Fig. 4d) [33, 59, 68, 95, 226, 251]. An important feature of these glial scars is the interaction of reactive astrocytes with other cell types, in particular ﬁbromeningeal and other glial cells (Fig. 4d) [31, 95], and the deposition of a dense collagenous extracellular matrix that contains many molecular cues that inhibit axonal and cellular migration [219]. Triggering insults include pene- trating trauma, severe contusive trauma, invasive infections or abscess formation, neoplasm, chronic neurodegenera- tion, systemically triggered inﬂammatory challenges. It is noteworthy that the glial scar formation is associated with substantive tissue reorganization and structural changes b Fig. 4 Schematic representations that summarize different gradations of reactive astrogliosis. a Astrocytes in healthy CNS tissue. b Mild to moderate reactive astrogliosis comprises variable changes in molec- ular expression and functional activity together with variable degrees of cellular hypertrophy. Such changes occur after mild trauma or at sites distant from a more severe injury, or after moderate metabolic or molecular insults or milder infections or inﬂammatory activation. These changes vary with insult severity, involve little anatomical overlap of the processes of neighboring astrocytes and exhibit the potential for structural resolution if the triggering insult is removed or resolves. c Severe diffuse reactive astrogliosis includes changes in molecular expression, functional activity and cellular hypertrophy, as well newly proliferated astrocytes (with red nuclei in ﬁgure), disrupting astrocyte domains and causing long-lasting reorganization of tissue architecture. Such changes are found in areas surrounding severe focal lesions, infections or areas responding to chronic neurodegenerative triggers. d Severe reactive astrogliosis with compact glial scar formation occurs along borders to areas of overt tissue damage and inﬂammation, and includes newly proliferated astrocytes (with red nuclei in ﬁgure) and other cell types (gray in ﬁgure) such as ﬁbromeningeal cells and other glia, as well as deposition of dense collagenous extracellular matrix. In the compact glial scar, astrocytes have densely overlapping processes. Mature glial scars tend to persist for long periods and act as barriers not only to axon regeneration but also to inﬂammatory cells, infectious agents, and non-CNS cells in a manner that protects healthy tissue from nearby areas of intense inﬂammation that are long lasting and persist long after the triggering insult may have resolved. The ﬁndings summarized here show that there are pro- nounced differences along the continuum of potential responses of reactive astrocyte to insults of different kinds and severities. These differences are likely to be of con- sequence when considering the functions and impact of reactive astrogliosis on CNS disorders and pathologies, as discussed below. The role of astrocyte proliferation in reactive astrogliosis and glial scar formation The contribution of astrocyte proliferation to reactive astrogliosis warrants speciﬁc consideration. The wide- spread and often exclusive use of GFAP as a marker for astrocytes has led to a tendency to overestimate the con- tribution of astrocyte proliferation to reactive astrogliosis. As discussed above, many astrocytes in healthy CNS do not express GFAP at immunohistochemically detectable levels, or express only very low levels (Figs. 3a, 4a). During mild or moderate astrogliosis, there is a marked up regulation of GFAP expression as well as cellular hyper- trophy in essentially all astrocytes, which can lead to the false impression of an increase in astrocyte number because more astrocytes are immunohistochemically stained and the larger astrocytes seem more densely packed (Figs. 3b, 4b). In healthy CNS tissue, astrocyte turnover is 123