Acta Neuropathol (2010) 119:7–35 for astrocytes is suggested by studies in transgenic mice in which ablation of reactive astrocytes after CNS trauma prevented the normally occurring repair of the BBB and grafts of normal astrocyte were able to restore BBB repair [33]. It is not yet known whether a primary dysfunction of astrocytes or reactive astrocytes could lead to loss of BBB integrity. It is possible that loss of astrocyte production of a potential BBB inductive molecule, such as GSNO [208], or astrocyte over production of BBB disrupting molecules might lead to loss of BBB integrity [69, 188]. Hepatic encephalopathy Hepatic encephalopathy can lead to mild to severe neuro- psychiatric symptoms, brain edema with increased intracranial pressure associated with cerebellar tonsillar, uncal and/or central diencephalic herniation, and coma. Astrocytes are now recognized as playing a central role in the pathophysiology of hepatic encephalopathy [166]. The brain edema is largely a result of astrocyte swelling, which in turn is caused by astrocytic uptake of NH4?. Although astrocyte uptake of NH4? is regarded initially as a neuro- protective mechanism, it also drives the synthesis of glutamine from glutamate by glutamine synthetase, resulting in changes in transmitter homeostasis that may contribute to behavioral symptoms. The accumulation of glutamine in astrocytes also leads to osmotic stress that results in astrocyte swelling and progressive cytotoxic edema [107, 166, 193]. Metabolic disorders Niemann-Pick type C, is an inherited neurovisceral lipid storage disorder caused by loss of function mutations of the membrane-bound protein, NPC1, which is thought to play a role in trafﬁcking of cholesterol and other lysosomal cargo. In the CNS, NPC1 is expressed predominantly in perisy- naptic astrocyte processes that are closely associated with nerve terminals, the earliest site of degeneration in the disease, suggesting that disruption of NPC1-mediated vesicular trafﬁcking in astrocytes may be linked to neuro- nal degeneration [178]. It is interesting that selective restoration of expression of Npc1 in GFAP-positive astro- cytes in Npc1-/- mice enhanced survival and decreased neuronal storage of cholesterol in the CNS, while restora- tion of expression of Npc1 in GFAP-positive in enteric glial cells in Npc1-/- mice ameliorated enteric neuropa- thology [110, 265]. Aceruloplasminemia is an inherited disorder of iron metabolism caused by the lack of ceruloplasmin activity. The neuropathological hallmarks are excessive iron depo- sition, neuronal loss, bizarrely deformed astrocytes, and numerous ‘grumose’ or foamy spheroid bodies. In the 23 CNS, ceruloplasmin is largely produced by perivascular astrocytes and exhibits a ferroxidase activity that inhibits iron-associated lipid peroxidation and hydroxyl radical formation [174]. Astrocytes play key roles in iron traf- ﬁcking and the detoxiﬁcation of iron-mediated free radicals. Lack of ceruloplasmin causes direct oxidative stress on astrocytes. In aceruloplasminemia, deformed astrocytes accumulate ferric iron and the antioxidative ability of astrocytes is compromised, leading to secondary neuronal cell death [174]. Astrocyte abnormalities and CNS malformations or lesions are also associated with the rare genetic disorders, congenital glutamine synthetase deﬁciency [88], and pyruvate carboxylase deﬁciency [79]. Alexander disease and other leukodystrophies Alexander disease is a genetic disorder of astrocytes caused by a dominant, gain-of-function mutation of the gene encoding GFAP [25]. Astrocytes are hypertrophied and exhibit numerous, characteristic Rosenthal ﬁbers that are aggregates of GFAP and are therefore prominently GFAP- immunoreactive [25, 247]. There is particular involvement of the white matter and patients exhibit macrocephaly, seizures, psychomotor disturbances, spasticity, and pre- mature death. Over expression of GFAP in transgenic mice causes a fatal encephalopathy similar to the human con- dition [143]. It is interesting to note that high densities of Rosenthal ﬁbers, comparable to those seen in Alexander’s disease, have been described in the context of pronounced astrocytic abnormalities in severe FCD with intractable pediatric epilepsy (Fig. 6b) [111] (see above). Megaloencephalic leukoencephalopathy with subcorti- cal cysts (MLC) is an autosomal recessive, progressive white matter disease in children, characterized by myelin splitting and intramyelinic vacuole formation and caused by mutations in the MLC1 gene. In the CNS, the MLC1 protein is speciﬁcally expressed in distal astroglial pro- cesses in perivascular, subependymal, and subpial regions. This localization plus the transmembrane domains of the protein, support the possible transport functions of MLC1, possibly across the blood–brain and brain-cerebrospinal ﬂuid barriers [21, 210]. Vanishing white matter disease (VWM) is a rare auto- somal recessive leukoencephalopathy linked to mutations in translation initiation factor 2B (eIF2B). VWM lesions in vivo lack GFAP expressing astrocytes. Mutations in the eIF2B genes are thought to impair the ability of cells to regulate protein synthesis. RNAi targeting of EIF2B5 severely compromised the generation of GFAP expressing astrocytes from normal human glial progenitors, raising the possibility that a deﬁciency in astrocyte function may contribute to the loss of white matter in VWM [55, 244]. 123