Astrocytes tile the entire CNS in a contiguous and essentially 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 individual 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 astrocytes in rodents [170].

Astrocytes express potassium and sodium channels and can exhibit evoked inward currents, but unlike neurons, astrocytes 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 triggered by transmitters (including glutamate and purines) 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 signaling enables astrocytes to play a direct role in synaptic transmission is discussed below. It is also noteworthy that astrocytes can couple to neighboring astrocytes through gap junctions (Fig. 2a) formed by connexins, and that the gap junctional coupling of astrocytes into multicellular networks may play a role in both normal function and CNS disorders [162, 212].

The developmental generation of astrocytes tends to occur after the initial production of neurons in many CNS regions. Nevertheless, astrocytes exert a number of important functions during development of both gray and white matter. Molecular boundaries formed by astrocytes take part in guiding the migration of developing axons and certain neuroblasts [186]. In addition, substantive evidence is accumulating that astrocytes are essential for the formation and function of developing synapses by releasing molecular signals such as thrombospondin [15, 43, 243]. Astrocytes appear also to influence developmental synaptic pruning by releasing signals that induce expression of complement C1q in synapses and thereby tag them for elimination by microglia [15, 230]. As regards the development of white matter, the loss or dysfunction of astrocyte connexins and gap junctions leads to dysmelination [131].

Astrocytes make extensive contacts with (Fig. 1a, b) and have multiple bidirectional interactions with blood vessels, including regulation of local CNS blood flow. Recent findings show that astrocytes produce and release various molecular mediators, such prostaglandins (PGE), nitric oxide (NO), and arachidonic acid (AA), that can increase or decrease CNS blood vessel diameter and blood flow in a coordinated manner [86, 102]. Moreover, astrocytes may be primary mediators of changes in local CNS blood flow in response to changes in neuronal activity [112]. Astrocytes have processes in contact with both blood vessels and synapses (Fig. 2a). Via these contacts, astrocytes titrate blood flow in relation to levels of synaptic activity, as demonstrated recently in the visual cortex where fMRI detected changes in blood flow in response to visual stimuli were shown to be dependent on astrocyte function [211, 260].

Astrocyte processes envelop essentially all synapses [27, 183] and exert essential functions in maintaining the fluid, ion, pH, and transmitter homeostasis of the synaptic interstitial fluid in a manner that is critical for healthy synaptic transmission (Fig. 2a). Astrocyte processes are rich in the aquaporin 4 (AQP4) water channel and in transporters for the uptake of K⁺ [212, 220, 264]. Astrocyte membranes have different means of proton shuttling, including the Na⁺/H⁺ exchanger, bicarbonate transporters, monocarboxylic acid transporters, and the vacuolar-type proton ATPase [168]. AQP4 water channels are densely clustered along astrocyte processes that contact blood vessels and play a critical role in regulating fluid homeostasis in healthy CNS and play roles in both vasogenic and cytotoxic edema as discussed below. Astrocyte processes at synapses also play essential roles in transmitter homeostasis by expressing high levels of transporters for neurotransmitters such as glutamate, GABA, and glycine that serve to clear the neurotransmitters from the synaptic space [205, 212]. After uptake into astrocytes, the transmitters are converted by enzymes such as glutamine synthetase into precursors such as glutamine and recycled back to synapses for reconversion into active transmitters (Fig. 2a). Networks of astrocytes linked together by gap junctions are thought to be able to rapidly dissipate small molecules such as potassium and glutamate and prevent their potentially detrimental accumulation (Fig. 2a) [212].

A growing body of evidence also now indicates that astrocytes make important contributions to CNS metabolism. Astrocytes, which have processes that on the one hand contact blood vessels and on the other hand contact neuronal perikarya, axons (at nodes of Ranvier), and synapses, are well positioned to take up glucose from blood vessels and furnish energy metabolites to different neural elements in gray and white matter (Fig. 2a). Although it was known for many years that astrocytes are the principal storage sites of glycogen granules in the CNS and that the greatest accumulation of astrocytic glycogen occurs in areas of high synaptic density [183, 184], the functional contribution of these stores was originally discounted [27]. Compelling evidence now demonstrates that astrocytic glycogen utilization can sustain neuronal activity during hypoglycemia and during periods of high neuronal activity [27, 231]. In this regard, it is noteworthy that astrocyte glycogen content can be modulated by transmitters such as glutamate [27] and that glucose metabolites can be passed across gap junctions in a manner that is regulated by glutamate and neuronal activity [200]. Other lines of evidence indicate that during hypoglycemia, astrocyte glycogen breaks down to lactate that is transferred to adjacent neural elements (both synapses in gray matter and axons in white matter) where it is used aerobically as fuel [27, 28, 181, 252]. In addition, computer-based modeling studies suggest that during periods of high neuronal activity, inhibition of phosphofructokinase leads to impairment of neuronal glycolysis, with the consequence that lactate effluxed from astrocytes becomes the preferred energy substrate for neurons [171].

The blood brain barrier (BBB) is a diffusion barrier that impedes the influx into brain parenchyma of certain molecules on the basis of polarity and size [1, 11]. The principal cellular constituents of the BBB are cerebral capillary endothelial cells that form tight junctions and are surrounded by a basal lamina, perivascular pericytes, and astrocyte endfeet. The role of pericytes in BBB function is not well studied and the role of astrocytes is controversial. The main functional components of the BBB are the endothelial tight junctions [1, 11]. Numerous lines of in vitro evidence indicate that astrocytes can induce barrier properties in cerebral and other endothelial cells as well as in related epithelial, arguing in favor of a role for astrocytes in BBB induction [1, 11, 17, 208]. In contrast, certain aspects of the BBB become functional in vivo before the appearance of astrocytes during development [93, 206]. In this regard, it is interesting to note that embryonic neural progenitor cells are able to induce BBB properties in cerebral endothelial cells [255]. Other studies suggest a role for astrocytes in regulating BBB properties of cerebral endothelial in vivo in adult mice through specific BMP signaling mechanisms on astrocyte endfeet that when disrupted cause BBB leaks [6]. In addition, both astrocytes and related enteric glial cells are able to induce barrier properties in gut epithelial cells and the molecule GSNO has been identified as a molecular mediator of this effect [208]. Additional studies will be needed to clarify the roles of astrocytes and pericytes in BBB function and to identify molecular mediators that may induce BBB properties in cerebral endothelia. It is possible that different cell types provide such factors at different times during development and in healthy or injured CNS.

The increasing awareness of the complexity, importance, and diversity of astrocyte functions is giving rise to a growing interest in the potential for specialization and heterogeneity among astrocytes [96]. The notion of astrocyte heterogeneity is not new. Numerous anatomical distinctions have long been recognized among gray (protoplasmic) and white (fibrous) matter astrocytes in different CNS regions [191], but these have long been over looked or discounted. In addition, there is a long-standing recognition of an extended family of astroglial cells that share similarities with, but also exhibit differences to, protoplasmic and fibrous astrocytes, including Müller glia in the retina, Bergmann glia of the cerebellum, tanycytes at the base of the third ventricle, pituicytes in the neurohypophysis, cribrosocytes at the optic nerve head, and others. These different cell types express various astrocyte-related molecules such as GFAP, S100β, glutamine synthetase and others, and exert functions similar to astrocytes in manners specialized to their locations. In addition, these different types of astroglial cells share with astrocytes the ability to become reactive in response to CNS insults and these cells have the potential to play important roles in pathological changes in their specific locations as discussed below. As regards protoplasmic and fibrous astrocytes, various lines of evidence suggest that there is considerable molecular, structural, and potentially functional diversity of astrocytes at both the regional and local levels, but such investigations are at an early stage [10, 96]. In this context it is interesting to note that the number, complexity, and diversity of astroglial cells associated with neurons has increased considerably with evolution, such that the ratio of astrocytes to neurons is 1:6 in worms, 1:3 in rodent cortex, and 1.4:1 in human cortex, implying that astrocyte roles increase in importance with sophistication of neural tissue [162]. The human cerebral neocortex contains multiple subtypes of astrocytes, including types that do not appear to exist in rodent cortex [170]. As molecular markers become more sophisticated, it seems likely that astrocytes will be revealed to be considerably more heterogeneous than thus far imagined. Such information is likely to impact on concepts about astrocyte roles in both health and disease.

Recent studies have identified specific morphological and chemical phenotypes of neural stem cells (NSC) in embryonic, juvenile, and adult brain. In the embryonic brain, it is now clear that radial cells are NSC that give rise to cortical pyramidal neurons [116, 134, 164]. As these radial cells mature, they adopt GFAP expression and some give rise to GFAP-expressing radial NSC that persist in juvenile and adult forebrain, while others become astrocytes [116, 122, 142]. Some GFAP-expressing radial NSC remain constitutively active throughout life in the subependymal (or subventricular) zone of the lateral ventricles and in the subgranular zone of the hippocampal dentate gyrus, where they are the predominant source of adult neurogenesis [56, 78, 103, 214]. Based almost entirely on the observation that these adult NSC express GFAP, they have been referred to by some authors as a ‘sub-type’ of astrocyte [56, 116], but it is not clear that such a nomenclature is either warranted or useful [14, 84, 153]. There is ample evidence that GFAP is not an exclusive marker of astrocytes. Moreover, as described above, protoplasmic and fibrous astrocytes are highly differentiated and specialized cells that exert a wide variety of complex activities essential for neural function in the healthy CNS, and at present there is no evidence that GFAP-expressing adult radial NSC exert any of the complex functions of mature differentiated protoplasmic and fibrous astrocytes. In addition, there is clear evidence that mature adult astrocytes are not neurogenic. Differentiated astrocytes in uninjured mature cerebral cortex do not exhibit neurogenic potential either in vivo or in vitro [104]. Even proliferating reactive astrocytes after CNS trauma give rise only to other astrocytes and do not spontaneously exhibit multipotent neurogenic potential unless they are reprogrammed genetically or by exposure to high doses of specific growth factors in vitro [29, 30]. In addition, GFAP-expressing NSC differ in morphology (radial phenotype), chemical phenotype (LeX and nestin expression), and physiological characteristics from protoplasmic and fibrous astrocytes [78, 104, 126]. Thus, the majority of currently available evidence argues that juvenile and adult NSC share more similarities with embryonic radial NSC than with mature astrocytes. There seems to be no reason to label the multipotent neural progenitors that persist throughout life as a subtype of astrocyte, which risks the blurring of clear functional distinctions among cell types. Instead, it seems that clarity would best be served by referring to these progenitors simply as either juvenile or adult radial NSC, in keeping with their derivation and phenotype. It has been argued that it may be useful to return to the nomenclature of early neuroanatomists who referred to such radial progenitor cells as ‘neuroepithelial cells’ rather than glia [14, 153]. Regardless of nomenclature, the presence in certain forebrain areas of GFAP-expressing cells that have constitutive multipotent NSC potential throughout life has important implications for concepts regarding various CNS disorders, in particular CNS neoplasms, as discussed below.

The contribution of astrocyte proliferation to reactive astrogliosis warrants specific consideration. The widespread and often exclusive use of GFAP as a marker for astrocytes has led to a tendency to overestimate the contribution of astrocyte proliferation to reactive astrogliosis. As discussed above, many astrocytes in healthy CNS do not express GFAP at immunohistochemically detectable levels, or express only very low levels (Figs. 3a, ​a,4a).4a). During mild or moderate astrogliosis, there is a marked up regulation of GFAP expression as well as cellular hypertrophy in essentially all astrocytes, which can lead to the false impression of an increase in astrocyte number because more astrocytes are immunohistochemically stained and the larger astrocytes seem more densely packed (Figs. 3b, ​b,4b).4b). In healthy CNS tissue, astrocyte turnover is low and there are few proliferating or newly generated astrocytes and it appears that the majority of astrocytes are post-mitotic and long-lived [33, 45, 97, 167]. Experimental analysis of cell proliferation indicates that GFAP up regulation and hypertrophy can occur in mild or moderate astrogliosis in the absence of proliferation and increase in cell number [226]. The appearance of newly proliferated astrocytes occurs in severe diffuse reactive astrogliosis and severe reactive astrogliosis with compact glial scar formation as discussed above (Figs. 3c, ​c,4c,4c, d). In human specimens, actively dividing reactive astrocytes have been particularly reported in association with infection and acute demyelinating lesions [45]. The source of newly divided scar-forming astrocytes is not well established, and may include mature astrocytes that re-enter the cell cycle as well as progenitor cells in the local parenchyma or in the periventricular regions [30, 33, 37, 77, 133, 141, 226].

Many different types of intercellular signaling molecules are able to trigger reactive astrogliosis or to regulate specific aspects of reactive astrogliosis, including (1) large polypeptide growth factors and cytokines such as IL6, LIF, CNTF, TNFα, INFγ, Il1, Il10, TGFβ, FGF2, etc., (2) mediators of innate immunity such as lipopolysaccharide (LPS) and other Toll-like receptor ligands, (3) neurotransmitters such as glutamate and noradrenalin, (4) purines such as ATP, (5) reactive oxygen species (ROS) including nitric oxide (NO), (6) hypoxia and glucose deprivation, (7) products associated with neurodegeneration such as β-amyloid, (8) molecules associated with systemic metabolic toxicity such as NH₄⁺, and (9) regulators of cell proliferation such endothelin-1, as reviewed in detail elsewhere [226]. Such molecular mediators of reactive astrogliosis can be released by all cell types in CNS tissue, including neurons, microglia, oligodendrocyte lineage cells, pericytes, endothelia, and other astrocytes, in response to all forms of CNS insults, ranging from subtle cellular perturbations that release some of the specific factors just listed, to cell stretching as might be encountered during acceleration/deceleration CNS injury and which releases ATP, to intense tissue injury and cell death that release various intracellular molecules that signal intense tissue damage (Fig. 2b) [226]. It is also becoming clear that different molecular, morphological, and functional changes in reactive astrocytes are specifically controlled by inter- and intra-cellular signaling mechanisms that reflect the specific contexts of the stimuli and produce specific and gradated responses of reactive astrogliosis [226]. For example, the different intracellular signaling pathways associated with STAT3, NFκB, SOCS3, Nrf2, cAMP, Olig2 are implicated in mediating different aspects or different degrees of reactive astrogliosis such as GFAP up regulation, cell hypertrophy, proliferation, and pro- or anti-inflammatory effects [226]. Molecular triggers that lead to proliferation of reactive astrocytes in vivo are incompletely characterized but include EGF, FGF, endothelin 1, and ATP [77, 121, 161].

Concepts about reactive astrogliosis have long been dominated by the recognition over 100 years ago that scars formed by reactive astrocytes inhibit axon regeneration and by the interpretation that this scar formation was the main impediment to functional recovery after CNS injury or disease [192]. The ensuing over 100-year-long emphasis on glial scar formation as an inhibitor of axon regeneration has often led to a generalized negative view of reactive astrogliosis per se, and there has been a tendency among certain authors to typecast the entire process of reactive astrogliosis as a uniformly negative and maladaptive phenomenon that unavoidably causes neurotoxicity, inflammation, or chronic pain. This stereotyped viewpoint has sometimes led to the simplistic notion that total inhibition of reactive astrogliosis can be regarded as a therapeutic strategy. This absolutely negative viewpoint of reactive astrogliosis is no longer tenable and it is now clear from many different lines of experimental evidence that there is a normal process of reactive astrogliosis that exerts essential beneficial functions and does not do harm. As reviewed in detail elsewhere [226], many studies using transgenic and experimental animal models provide compelling evidence that reactive astrocytes protect CNS cells and tissue by (1) uptake of potentially excitotoxic glutamate [33, 198, 234], (2) protection from oxidative stress via glutathione production [42, 216, 234, 245], (3) neuroprotection via adenosine release [125], (4) protection from NH₄⁺ toxicity [193], (5) neuroprotection by degradation of amyloid-beta peptides [113], (6) facilitating blood brain barrier repair [33], (7) reducing vasogenic edema after trauma, stroke or obstructive hydrocephalus [33, 264], (8) stabilizing extracellular fluid and ion balance and reducing seizure threshold [264], and (9) limiting the spread of inflammatory cells or infectious agents from areas of damage or disease into healthy CNS parenchyma [33, 59, 68, 95, 123, 156, 175, 251].

Of particular interest as regards functions of reactive astrocytes, is recent evidence that reactive astrogliosis and glial scar formation play essential roles in regulating CNS inflammation [226]. In response to different kinds of stimulation, reactive astrocytes can make many different kinds of molecules with either pro- or anti-inflammatory potential [60, 108] and reactive astrocytes can exert both pro- and anti-inflammatory effects on microglia [67, 148]. A large body of experimental studies indicates that reactive astrocytes can exert both pro- and anti-inflammatory regulatory functions in vivo in a context dependent manner that is regulated by specific molecular signaling pathways [226]. A functional model, which may reconcile the apparent paradox that reactive astrocytes have the potential to exert both pro- and anti-inflammatory activities, is that reactive astrocytes exert different activities at different times after insults, or in different geographical locations in relation to lesions, as determined by context-specific signaling mechanisms. For example, reactive astrocytes may exert pro-inflammatory roles at early times after insults and in the center or immediate vicinity of lesions, but exert anti-inflammatory roles at later times and at the borders between lesions and healthy tissue. In cases of severe lesions, reactive astrocytes may form scars that act as cell migration barriers around the borders of areas where intense inflammation is needed and thereby restrict the spread of inflammatory cells and infectious agents into adjacent healthy tissue (Fig. 4d) [225, 226]. Together, these findings indicate that there is a normal process of reactive astrogliosis and glial scar formation that exerts various beneficial functions including protecting neural cells and function, restricting the spread of inflammation and infection, and promoting tissue repair. It is important to distinguish this normal process from the potential for dysfunction of reactive astrocytes to contribute to CNS disorders.

Astrocytes have several mechanisms through which they can influence water balance and the potential for edema, including ion channels and pumps, the water channel AQP4 and the production of molecules such as vascular endothelial growth factor (VEGF) or NO that influence endothelial cell permeability. The role of astrocytes in edema is complex and likely to be context dependent. Although excess uptake of water through AQP4 on astrocyte endfeet can lead to cytotoxic edema [135, 157, 264], the loss of astrocytes or the failure of astrocyte AQP4 channels can also lead to vasogenic edema or accumulation of extracellular fluid [33, 157, 177, 264].

Integrity of the BBB is lost after many types of CNS insults including trauma and stroke. The role of astrocytes in loss or repair of BBB functions is not well understood. A role 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 can lead to mild to severe neuropsychiatric 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 neuroprotective 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].

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 participate in regulation of CNS inflammation by responding to and producing a wide variety of cytokines. These mechanisms 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 TNFα that alter neuronal membrane receptor levels, all of which can amplify neuronal excitability [147]. The molecules involved in these emerging multi-cellular signaling interactions are providing novel targets for analgesic therapeutic strategies.

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.

Reactive astrogliosis is a well-known feature of Alzheimer’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 surround 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 (Aβ42) as well as truncated forms [159, 239]. Of considerable interest are reports that reactive astrocytes can take up and degrade extracellular deposits of Aβ42 [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.

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 astrogliosis exhibits some characteristics of severe diffuse reactive astrogliosis (Figs. 3c, ​c,4c),4c), it is not clear whether astrocytes play an active role in prion replication and disease pathogenesis or whether astrogliosis is largely reactive to the disease process in other cell types [115]. It is interesting that the hippocampal neuronal degeneration associated with experimental ablation of reactive astrocytes has a vacuolar appearance with similarities to spongiform changes [33].

The role of astrocytes in Parkinson’s disease and related syndromes is sparsely investigated and poorly understood [140]. Reactive astrogliosis is generally mild or moderate and rarely severe in autopsy specimens of substantia nigra from Parkinson’s disease patients [72, 149]. Astrocytes have been implicated as potentially exerting both neurotoxic and neuroprotective activities in Parkinson’s disease. Experimental studies show that astrocytes take up the Parkinson’s syndrome causing molecule, MPTP, from the blood stream and convert it to neurotoxic MPP⁺ and may similarly convert other environmental molecules that have been implicated in dopaminergic toxicity [54, 187]. On the other hand, activation of the transcription factor Nrf2 selectively in astrocytes protects mice from MPTP-induced Parkinsonism by activating anti-oxidative response pathways [40]. Rare mutations in Nurr1 lead to familial Parkinson’s disease, and expression of Nurr1 in astrocytes suppresses production of potentially toxic molecules and protects against loss of dopaminergic neurons [203]. Recent findings also show that subpopulations of astrocytes express disease-related proteins such as α-synuclein, parkin and phosho-tau to different levels and in different combinations in Parkinson’s disease, multiple-system atrophy, and progressive supranuclear palsy [227], but the roles of astrocytes in these conditions are not yet defined.

Evidence is available suggesting two quite different potential roles for astrocytes in amyotrophic lateral sclerosis (ALS) or motor neuron disease, through either the loss of a neuroprotective function or the gain of a neurotoxic effect. Sporadic ALS is characterized by selective loss or dysfunction of astrocyte glutamate transporters in spinal cord and cerebral cortical areas that exhibit loss of lower and upper motor neurons [73, 136, 194, 197], suggesting that increased glutamate excitotoxicity may contribute to motor neuron death and raising the possibility of different types of potential interventions. A high-throughput screen of small molecules has identified that certain β-lactam antibiotics can stimulate the expression of glutamate transporters by astrocyte and thereby enhance glutamate uptake sufficiently to reduce excitotoxicity, and provide neuroprotection in animal models of stroke and ALS [199]. The β-lactam antibiotic, Ceftriaxone, began stage 3 clinical trials in May 2009 to determine efficacy in reducing excitotoxicity and neurodegeneration in ALS. Focal grafts of healthy astrocytes are reported to be neuroprotective in an animal model of ALS, suggesting that transplantation of astrocytes may be a potential therapeutic strategy [120]. From a different perspective, astrocytes may also exhibit neurotoxic dysfunction in ALS. Approximately 20% of familial ALS cases, and about 5% of apparently sporadic cases, exhibit missense mutations of the gene encoding superoxide 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 production 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 molecules and the mechanisms leading to their production are not yet clear.

Tauopathies are primarily associated with intracellular filamentous deposits in neurons that lead to functional disturbances [83]. Nevertheless, there is evidence to suggest 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].

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 Huntington’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].

Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder with neuropsychologic deficits and predisposition to Schwannomas and astrocytomas caused by mutations in the NF1 gene [2, 9]. Reduced expression of glutamate transporters have been reported in reactive astrocyte clusters in NF1 [263]. Changes in mTOR and PTEN-signaling pathways in Schwann cells and astrocytes may contribute to tumorigenesis in NF1 [50, 87].

The gastrointestinal tract is highly innervated and neuropathology of the enteric nervous system is emerging as a central feature of many gut diseases. Although most considerations of the enteric nervous system have focused on neuronal dysfunction, a large population of astrocyte-like glia populates gut muscle layers and the intestinal mucosa, and mounting new evidence points toward enteric glia, which express GFAP and share functional similarities with astrocytes, as active participants in gut pathology [207]. Various lines of experimental and neuropathological evidence are consistent with the possibility that enteric glia constitute a previously unrecognized disease target in pathologies associated with intestinal barrier dysfunction, notably inflammatory bowel disease, necrotizing enterocolitis, irritable bowel syndrome, diabetes, autoimmune disease, and neurotropic virus infection of the gut pathology [44, 207]. Experimental ablation of enteric glia leads to inflammatory bowel disease [32]. Both astrocytes and related enteric glial cells are able to induce barrier properties in gut epithelial cells, and S-nitrosoglutathione (GSNO) has been identified as one molecular mediator of this effect [208]. Thus, enteric glia, like astrocytes, appear to play essential roles in barrier functions during disease processes, particularly as regards regulating the spread of inflammation [49, 207, 226, 251].

There is now growing evidence that stellate shaped, GFAP-expressing cells in various tissues may have functions that are similar to those of astrocytes. For example, there is increasing evidence that GFAP-expressing pancreatic stellate cells play important roles in tissue repair, fibrosis, and scar formation [176]. Hepatic stellate cells not only express GFAP and have morphological appearance similar to astrocytes, but also contact hepatic sinusoids and blood vessels and may take part in hepatic immune processes [258, 259]. In this regard, it is particularly interesting that the liver, like the CNS, has a certain level of immune privilege [241], and that both CNS and liver have resident populations of macrophage-related cells (Kupfer cells in the liver and microglia in the CNS) as well as of stellate cells that participate in immune and inflammatory processes. In addition, there is evidence that GFAP-expressing mesangial cells in the kidney function as local modulators of innate and adaptive immune responses [209]. The increasing recognition that tissue-specific cells like astrocytes and stellate cells play essential roles in regulating local immune and inflammatory processes is likely to impact considerably on concepts about organ-specific vulnerability to autoimmunity and other inflammatory conditions.