dysfunctions can begin before detectable evidence of astrocyte reactivity (Key Figure, Figure 2H), as seen for example in a mouse model of HD, where early dysregulation of extracellular K+ homeostasis contributed to neuronal hyperexcitability and symptom onset [86]. Alternatively, disease-induced cell-autonomous astrocyte dysfunctions can, in a disorder specific manner, either blunt, amplify, or change normal astrocyte reactivity responses, e.g. resulting in loss of essential astrocyte functions and increased neurodegeneration [56], gain of detrimental astrocyte effects and excess inflammation [25], or seizure genesis [88] im mouse or zebrafish experimental models. It is important to distinguish normal astrocyte reactivity from such astrocyte disease states (Key Figure, Figure 2G). Historically there has been a widespread misbelief that normally occurring astrocyte reactivity is a maladaptive event that per se, causes tissue damage and should be globally attenuated. There is no evidence for this misbelief. Instead, there is a need to differentiate physiologically adaptive astrocyte reactivity from disease-induced astrocyte dysfunctions, and to target dysfunctions in a context specific manner.
