24 Glaucoma Glaucoma is characterized by unexplained loss of retinal ganglion neurons and by the reactive gliosis of astrocytes and related Mu¨ller cells in the retina, and the reactivity of astrocytes that surround ganglion cell axons in the optic nerve head. It is not clear whether the reactive gliosis in the retina is merely a response to a process afﬂicting the ganglion neurons or whether the gliosis contributes to that degeneration by loss of glial supportive functions, such as glutamate uptake, or contribution of degenerative effects such as production of reactive oxygen species [26, 109]. The optic nerve head, where the optic nerve emerges from the eye, is an area where several tissues meet and the area may be under particular stress and ﬂux during increases in intraocular pressure as are often associated with glaucoma. Astrocytes in the optic nerve head differ from white and gray matter astrocytes and have a distinct appearance and morphology. In rodents, optic nerve astrocytes are spatially aligned to ensheathe axons in bundles in a unique arrangement that provides essential structural support for the axons [232]. In primates, optic head astrocytes exhibit a similarly specialized morphology and provide additional structural support by secreting an extracellular matrix referred to as the lamina cribrosa [94, 262]. Various lines of evidence suggest that an early pre- cipitating event in glaucoma may be disturbances of axon– astrocyte interactions at the optic nerve head (perhaps as a consequence of increased stresses caused by raised intra- ocular pressure), which in turn lead to axonal damage and subsequent retrograde degeneration of retinal ganglion neurons [94, 98, 262]. Neuropathic pain Compelling evidence now indicates that pain signaling in the spinal cord dorsal horn involves interactions among microglia, astrocytes and neurons [147]. As discussed earlier, astrocytes can inﬂuence synaptic activity in a variety of direct and indirect ways and astrocytes partici- pate in regulation of CNS inﬂammation by responding to and producing a wide variety of cytokines. These mecha- nisms provide the basis for astrocyte involvement in both normal and pathological pain signaling. There is a growing body of evidence that astrocytes, which are chronically reactive in the dorsal horn due to local cellular interactions, have the potential to contribute to and exacerbate chronic and neuropathological pain in various ways, including release of neurotransmitters and neuromodulators such as glutamate, NO and PGE or through release of cytokines like TNFa that alter neuronal membrane receptor levels, all of which can amplify neuronal excitability [147]. The molecules involved in these emerging multi-cellular 123 Acta Neuropathol (2010) 119:7–35 signaling interactions are providing novel targets for analgesic therapeutic strategies. Migraine Prolonged cortical spreading depression is thought to play a fundamental role in the pathophysiology of migraine and can be caused by excessive synaptic glutamate release, or by decreased removal of glutamate and potassium from the synaptic cleft [204]. Familial hemiplegic migraine type 2, an autosomal dominant form of migraine with aura, has been associated with four distinct mutations in the alpha2- subunit of the Na?,K?-ATPase that is expressed primarily in astrocytes. The mutations all result in decreased activity of the Na?,K?-pump in astrocytes [36], which in turn may lower the threshold for cortical spreading depression and migraine attacks. Alzheimer’s disease Reactive astrogliosis is a well-known feature of Alzhei- mer’s disease (AD), but its roles in AD are not well understood. Reactive astrogliosis tends to be focal in AD such that reactive astrocytes are intimately associated with amyloid plaques or diffuse deposits of amyloid and sur- round them with dense layers of processes as if forming miniature scars around them (Fig. 7a), perhaps to wall them off and act as neuroprotective barriers. Reactive astrocytes can contain substantial amounts of different forms of amyloid beta, including amyloid beta 1–42 (Ab42) as well as truncated forms [159, 239]. Of consid- erable interest are reports that reactive astrocytes can take up and degrade extracellular deposits of Ab42 [261] and that this function is attenuated in ApoE-/- astrocytes [113], suggesting that reactive astrocytes functions or dysfunctions could play a role in the progression and severity of AD. The intensity of reactive astrogliosis, as determined by GFAP levels, has been reported to increase in parallel with increasing progression of Braak stages in AD, while concomitantly the levels of astrocyte glutamate transporters have been reported to decline, which may raise the vulnerability of local neurons to excitotoxicity [221]. Reactive astrocytes also exhibit increased expression of presenilin in sporadic AD [101, 254], but the consequences of this expression are not known. Transmissible spongiform encephalopathies Astrogliosis is prominent, diffuse, and intense throughout affected CNS regions in transmissible spongiform encephalopathies such as Creutzfeldt–Jakob disease (CJD) (Fig. 7b) and related prion diseases, especially if clinical symptoms have been of long duration. Although this