14 Reactive astrogliosis and glial scar formation Descriptive features of reactive astrogliosis and glial scars Although reactive astrogliosis is used widely as a patho- logical hallmark of diseased CNS tissue, deﬁnitions of reactive astrogliosis can vary considerably among authors and there are no widely accepted categories of intensity or severity. Based on a large body of observations in experi- mental animals, a deﬁnition of reactive astrogliosis has recently been proposed [226] that encompasses four key features: (1) reactive astrogliosis is a spectrum of potential molecular, cellular and functional changes in astrocytes that occur in response to all forms and severities of CNS injury and disease including subtle perturbations, (2) the changes undergone by reactive astrocytes vary with severity of the insult along a gradated continuum of pro- gressive alterations in molecular expression, progressive cellular hypertrophy, and in severe cases, proliferation and scar formation, (3) the changes of reactive astrogliosis are regulated in a context-speciﬁc manner by inter- and intra- cellular signaling molecules, (4) the changes undergone during reactive astrogliosis have the potential to alter astrocyte activities both through gain and loss of functions that can impact both beneﬁcially and detrimentally on surrounding neural and non-neural cells [226]. Here, we propose to apply and extend this deﬁnition to identifying different gradations of reactive astrogliosis and glial scar formation that may be encountered in histopathological examinations of human disorders (Figs. 3, 4). According to this deﬁnition, reactive astrogliosis is not an all-or-none response, nor is it a single uniform process, nor is it ubiquitously synonymous with scar formation. Instead, reactive astrogliosis is a ﬁnely gradated continuum of progressive changes in gene expression and cellular changes. Although the increasing severities of reactive astrogliosis transition seamlessly along a continuum, it is convenient for purposes of description and classiﬁcation to recognize three broad categories. Mild to moderate reactive astrogliosis In mild or moderate reactive astrogliosis there is variable up regulation of expression of GFAP and other genes [226], as well as hypertrophy of cell body and processes that can vary in degree but that occurs within the domains of individual astrocytes [257] without substantive inter- mingling or overlap of processes of neighboring astrocytes or loss of individual domains (Figs. 3b, 4b) [226]. There is little or no astrocyte proliferation in mild or moderate reactive astrogliosis; however, the up regulation of GFAP 123 Acta Neuropathol (2010) 119:7–35 expression in astrocytes that do not express detectable levels of GFAP in healthy tissue (Figs. 3a, 4a) can lead to the staining of more cells (Figs. 3b, 4b), sometimes giving the false impression of proliferation. Mild or moderate reactive astrogliosis is generally associated with mild non- penetrating and non-contusive trauma, diffuse innate immune activation (viral infections, system bacterial infections), and in areas that are some distance to focal CNS lesions. Because there is little or no reorganization of tissue architecture, if the triggering mechanism is able to resolve, then mild or moderate reactive astrogliosis exhibits the potential for resolution in which the astrocytes return to an appearance similar to that in healthy tissue [226]. The physiological consequences of mild or moderate reactive astrogliosis are not well understood. Severe diffuse reactive astrogliosis In severe diffuse reactive astrogliosis there is pronounced up regulation of expression of GFAP and other genes, together with pronounced hypertrophy of cell body and processes, as well as astrocyte proliferation, resulting in considerable extension of processes beyond the previous domains of individual astrocytes. As a result, there is substantive intermingling and overlapping of neighboring astrocyte processes with blurring and disruption of indi- vidual astrocyte domains (Figs. 3c, 4c). These changes can result in long-lasting reorganization of tissue architecture that can extend diffusely over substantive areas without the formation of dense, compact barriers as found in glial scars along borders to necrotic tissue (see below). Severe diffuse reactive astrogliosis is generally found in areas surrounding severe focal lesions, infections or areas responding to chronic neurodegenerative triggers. Severe reactive astrogliosis with compact glial scar formation Severe reactive astrogliosis with compact glial scar for- mation includes changes associated with milder forms, such as pronounced up regulation of GFAP and other genes, and pronounced hypertrophy of cell bodies and processes. In addition, glial scar formation progresses beyond these changes with groups of reactive astrocytes that exhibit pronounced overlapping of reactive astrocyte processes, obliteration of individual astrocyte domains, evidence of substantive astrocyte proliferation, and the clear formation of dense, narrow, and compact glial scars (Fig. 4d). Recent experimental evidence indicates that these astrocyte scars act as neuroprotective barriers to inﬂammatory cells and infectious agents, and that they form in particular along borders to severe tissue damage,