10 roles of astrocytes and reactive astrocytes. In addition, such studies are identifying potential candidates for additional, and better, molecular markers with which to identify astrocytes. One such candidate appears to be the protein Aldh1L1, whose promoter reliably targets the expression of reporter molecules such as GFP (green ﬂuorescent protein) to astrocytes and whose identiﬁcation by immunohisto- chemistry may provide a sensitive chemical marker for most if not all astrocytes in healthy tissue [15]. Anatomical organization Astrocytes tile the entire CNS in a contiguous and essen- tially non-overlapping manner that is orderly and well organized (Fig. 3a). There are no CNS regions devoid of astrocytes or closely related cells. Dye ﬁlling of individual cells and other anatomical techniques have demonstrated that in healthy CNS, individual protoplasmic astrocytes have essentially non-overlapping domains in gray matter, such that only the most distal tips of processes from indi- vidual astrocytes interdigitate with one another and thereby provide the substrate for formation of the gap junctions detected at the ultrastructural level [34, 91, 162, 172]. Similar individual astrocyte domains appear likely to exist in white matter, but this has not yet been as extensively reported on. Individual protoplasmic astrocytes typically extend from ﬁve to ten main stem branches, each of which gives rise to many ﬁnely branching processes that are evenly distributed throughout the astrocyte domain in the gray matter. In hippocampus or cortex many ﬁnely branching processes from a single astrocyte are estimated to contact several hundred dendrites from multiple neurons and to envelope 100,000 or more synapses [34, 91, 172]. It is also noteworthy that human astrocytes are larger, structurally more complex, and more diverse than astro- cytes in rodents [170]. Astrocyte physiology Astrocytes express potassium and sodium channels and can exhibit evoked inward currents, but unlike neurons, astro- cytes do not ‘ﬁre’ or propagate action potentials along their processes [162, 212]. However, this does not mean that astrocytes are physiologically ‘silent’. Astrocytes exhibit regulated increases in intracellular calcium concentration [Ca??]i that represent a form of astrocyte excitability [39, 46]. A large body of evidence is now available that these regulated increases in astrocyte [Ca??]i are of functional signiﬁcance in astrocyte–astrocyte as well as in astrocyte– neuron intercellular communication. Astrocyte [Ca??]i elevations can (1) occur as intrinsic oscillations resulting from Ca?? released from intracellular stores, (2) be trig- gered by transmitters (including glutamate and purines) 123 Acta Neuropathol (2010) 119:7–35 Fig. 3 Astrocyte morphology remote from CNS lesions and with different gradations of reactive astrogliosis. Brightﬁeld immunohis- tochemistry for GFAP counterstained with haematoxylin (H) in human autopsy specimens, surveys with details (boxed areas). a Appearance of astrocytes in tissue remote from a lesion and presumed healthy. Note that the territories of astrocyte processes do not overlap and that many astrocytes do not express detectable levels of GFAP. b Moderately reactive astrogliosis in which most (if not all) astrocytes have up regulated expression of GFAP and exhibit cellular hypertrophy, but with preservation of individual astrocyte domains and without pronounced overlap of astrocyte processes. c Severe diffuse reactive astrogliosis with pronounced up regulation of GFAP expression, astrocyte hypertrophy, astrocyte proliferation and pro- nounced overlap of astrocyte processes resulting in disruption of individual astrocyte domains. Scale bars surveys = 25 lm, details = 10 lm released during neuronal activity, (3) elicit the release from astrocytes of transmitters such as glutamate into the extracellular space and thereby trigger receptor mediated currents in neurons, and (4) be propagated to neighboring astrocytes [89, 162, 182, 215, 249]. Evidence that calcium