26 dismutase (SOD) that are dominantly inherited [201]. Recent ﬁndings show that expression of ALS mutant SOD in astrocytes (but not other cell types) leads to pro- duction by astrocytes of soluble molecules that are selectively toxic to motor neurons but not to spinal cord interneurons [53, 158], but the nature of the toxic mole- cules and the mechanisms leading to their production are not yet clear. Tauopathies Tauopathies are primarily associated with intracellular ﬁlamentous deposits in neurons that lead to functional disturbances [83]. Nevertheless, there is evidence to sug- gest that astrocyte tau pathology may also contribute to disease mechanisms. Filamentous tau aggregates can be observed in astrocytes in human disease and in animal models, and in animal models can disturb glutamate uptake and other astrocyte functions leading to focal neuronal degeneration [48, 71]. Huntington’s disease In Huntington’s disease, excitotoxicity has long been regarded as contributing to neuronal loss but the underlying mechanisms have been difﬁcult to elucidate [82]. There is increasing investigation of the potential for astrocytes contributions to dysfunction and degeneration in Hunting- ton’s disease through disturbances in glutamate uptake that can alter synaptic function and lead to excitotoxicity, or through abnormal production of neurotoxic molecules [127, 136]. Psychiatric disorders As it becomes increasingly clear that astrocytes play essential roles in synaptic mechanisms (see above), there is growing evidence that astrocyte functions and dys- functions may contribute to behavioral mechanisms and behavioral disorders [90]. For example, studies in experimental animals show that disruption of astrocyte- speciﬁc Na?,K?-ATPase results in increased anxiety- related behavior and impaired spatial learning in mice [154], and that astrocyte inﬂuences on synaptic functions are important in reward circuits, and may contribute to drug addiction [145]. Clinicopathological studies show that expression of astrocyte glutamate transporters has been found in prefrontal cortex of schizophrenic patients [137], and that the density of astrocytes is reduced in prefrontal cortex of patients with major depressive dis- orders [146, 189, 218]. Layer-speciﬁc reductions in GFAP-reactive have also been reported in astrocytes of the dorsolateral prefrontal cortex in schizophrenia [190] 123 Acta Neuropathol (2010) 119:7–35 and astrocyte roles in synaptic function are now central to certain hypotheses regarding schizophrenic disease mechanisms [19, 151]. The study of cellular neuropathology in psychiatric disorders is fraught with roadblocks. Morphologic abnormalities associated with behavioral illness may be extremely subtle and difﬁcult to detect. Individuals tend to die with a psychiatric disorder rather than of it (the exception to this being death by suicide), so that at the time of necropsy a past history of psychiatric illness may not be noted, or there may be changes in the brain secondary to longstanding other medical problems that ‘mask’ any intrinsic structural changes underlying a psychiatric illness. After many years of neuropsychiatric problems in a given patient, it may be difﬁcult or impossible to distinguish structural sequelae of pharma- cotherapy from structural changes that caused the illness. Astrocyte contributions to behavioral disorders are only beginning to be explored. In this regard, it should be considered that astrocytes may not show overt structural changes or changes in commonly used astrocyte markers in necropsy specimens. As histopathological molecular identiﬁcation techniques expand in breadth and become more sensitive, it may become possible (keeping in mind the caveats just mentioned) to detect astrocyte speciﬁc changes in molecular expression that are associated with speciﬁc disorders and clinical conditions. Brain tumors (primary or secondary) Astrocytes play a major role in the evolution of many common primary brain tumors, gliomas, and a less prom- inent, though signiﬁcant, role in the progression of metastases. From a practical diagnostic viewpoint, GFAP is a reliable immunohistochemical marker for staining sur- gically resected brain neoplasms to ascertain whether they have a signiﬁcant component of cells differentiating along astrocytic pathways [247]. The likelihood that a neoplasm is an ‘astrocytoma’ increases if cells throughout the tumor manifest atypical nuclear features (which can vary con- siderably in their degree of atypia) and also show some degree of cytoplasmic immunoreactivity with GFAP (Fig. 8a, b). Alternatively, abundant reactive astrocytes may show GFAP immunoreactivity within or surrounding non-glial tumors such as primary CNS lymphoma (Fig. 9a) or medulloblastoma (Fig. 9b) [247]. When GFAP-positive reactive astrocytes align themselves in a scar-like fashion along a non-glial (usually metastatic) tumor, the impression of a secondary neoplasm is strongly supported. Malignant astrocytic glioma, such as glioblastoma (astrocytoma WHO grade IV), are the most common and among the most lethal intracranial tumors [76, 128]. The cells of origin of astrocytic gliomas, whether potentially