Astrocyte reactivity was first recognized over 120 years ago. For decades it was regarded as a simple stereotypic response of little interest beyond being a marker of past or ongoing tissue pathology; and functional speculations were long centered around potential detrimental effects of ‘glial scars’ (but see Box 1) [1, 69]. The advent of transgenic technologies allowed causation-testing loss-of-function experiments to probe reactive astrocyte functions in vivo in specific injury or disease models. Early studies yielded surprises and unexpectedly revealed that genetically targeted ablation of proliferative border-forming reactive astrocytes in mice led to increased spread of inflammation, increased neuronal degeneration, failure of BBB repair and reduced recovery of certain neurological functions [11, 12]. Subsequent studies have confirmed and built on these observations. Although a detailed account is beyond the scope of this article, briefly, there are now numerous loss-of-function studies from multiple laboratories showing that transgenically attenuating astrocyte reactivity via selective deletion of a wide variety of different types of molecules, including membrane receptors, transcriptional regulators, or effector molecules, can exacerbate tissue injury and worsen functional outcome in models of
