Acta Neuropathol (2010) 119:7–35 glial scar formation play essential roles in regulating CNS inﬂammation [226]. In response to different kinds of stimulation, reactive astrocytes can make many different kinds of molecules with either pro- or anti-inﬂammatory potential [60, 108] and reactive astrocytes can exert both pro- and anti-inﬂammatory effects on microglia [67, 148]. A large body of experimental studies indicates that reactive astrocytes can exert both pro- and anti-inﬂammatory reg- ulatory functions in vivo in a context dependent manner that is regulated by speciﬁc molecular signaling pathways [226]. A functional model, which may reconcile the apparent paradox that reactive astrocytes have the potential to exert both pro- and anti-inﬂammatory activities, is that reactive astrocytes exert different activities at different times after insults, or in different geographical locations in relation to lesions, as determined by context-speciﬁc sig- naling mechanisms. For example, reactive astrocytes may exert pro-inﬂammatory roles at early times after insults and in the center or immediate vicinity of lesions, but exert anti-inﬂammatory roles at later times and at the borders between lesions and healthy tissue. In cases of severe lesions, reactive astrocytes may form scars that act as cell migration barriers around the borders of areas where intense inﬂammation is needed and thereby restrict the spread of inﬂammatory cells and infectious agents into adjacent healthy tissue (Fig. 4d) [225, 226]. Together, these ﬁndings indicate that there is a normal process of reactive astrogliosis and glial scar formation that exerts various beneﬁcial functions including protecting neural cells and function, restricting the spread of inﬂammation and infection, and promoting tissue repair. It is important to distinguish this normal process from the potential for dysfunction of reactive astrocytes to contribute to CNS disorders. Mechanisms for contributions of reactive astrogliosis to CNS disorders and pathologies Astrocytes and reactive astrocytes have the potential to impact on essentially all aspects of neural function through regulation of blood ﬂow, provision of energy substrates, or by inﬂuencing synaptic function and plasticity. Increasing evidence indicates that dysfunctions of the process of reactive astrogliosis and scar formation have the potential to contribute to, or to be primary causes of, CNS disease mechanisms either through loss of normal functions or through gain of detrimental effects [226]. Potential for loss of essential functions by reactive astrocytes As discussed earlier, in healthy neural tissue, astrocytes play critical roles in many functions, including regulation 17 of blood ﬂow, homeostasis of extracellular ﬂuid, ions and transmitters, energy provision, and regulation of synapse function, and synaptic remodeling (Fig. 2a). In addition, different types of transgenic deletion studies show that reactive astrocytes exert a number of essential beneﬁcial functions in response to CNS insults, including BBB repair, neural protection and restricting the spread of inﬂammatory cells, and infection. The disturbance or loss of these functions during the process of reactive astrogliosis has the potential to underlie neural dysfunction and pathology in various conditions including trauma, stroke, multiple sclerosis, and others. Genetic animal models are providing evidence for ways in which loss or attenuation of reactive astrocyte functions might worsen outcome after various kinds of CNS insults, for example, through excitotoxic neurodegeneration due to failure or attenuation of gluta- mate uptake [33, 198, 234] or increased inﬂammation or infection due to loss or failure of astrocyte barrier functions [33, 59, 68, 95, 251]. Clinical studies, discussed below, are also identifying a rapidly growing number of conditions that are precipitated by or exacerbated loss of functions by astrocytes or reactive astrocytes. Potential for gain of detrimental effects by reactive astrocytes In a manner analogous to inﬂammation, reactive astrogli- osis also has the potential to exert detrimental effects. The prototypical gain of a detrimental effect by reactive as- trogliosis and glial scar formation is the inhibition of axon regeneration, ﬁrst proposed over 100 years ago and now supported by extensive molecular and cell-biological evi- dence [219]. In addition, there is also evidence from both clinical (discussed below) and experimental studies that, under speciﬁc circumstances, astrocytes or reactive astro- cytes have the potential to exert a variety of other detrimental effects through gain of abnormal effects. For example, reactive astrocytes can be stimulated by speciﬁc signaling cascades (Fig. 2b) to gain of detrimental effects such as (1) exacerbating inﬂammation via cytokine pro- duction [22, 23], (2) producing neurotoxic levels of reactive oxygen species [92, 234], (3) releasing potentially excitotoxic glutamate [238], (4) potential contribution to seizure genesis [106, 240], (5) compromising blood brain barrier function due to VEGF-production [7], (6) causing cytotoxic edema during trauma and stroke through AQP4 over activity [264], and (7) contributing to chronic pain [147]. There also appears to be the potential for combi- natorial signaling cascades resulting from exposure to microbial antigens such as lipopolysaccharide (LPS), to markedly increase the production of potentially toxic molecules by astrocytes [67, 92]. Context-dependent acute or chronic combinatorial signaling events (Fig. 2b) 123