12 inducing the insertion of AMPA receptors at post-synaptic membranes [229]. Although it is not certain whether astrocytes or microglia are primary sources of TNFa in the CNS in vivo, the effects on synaptic function of astrocyte- derived growth factors and cytokines warrant further study. Astrocytes are also sources of neuroactive steroids (neu- rosteroids), including estradiol, progesterone and various intermediaries and metabolites that can have synaptic effects, particularly at GABAA receptors [80]. Energy and metabolism A growing body of evidence also now indicates that astrocytes make important contributions to CNS metabo- lism. 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 syn- apses, 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 glu- tamate 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 gly- colysis, with the consequence that lactate efﬂuxed from astrocytes becomes the preferred energy substrate for neurons [171]. Blood brain barrier The blood brain barrier (BBB) is a diffusion barrier that impedes the inﬂux into brain parenchyma of certain mol- ecules 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 123 Acta Neuropathol (2010) 119:7–35 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 dis- rupted 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. Astrocyte heterogeneity 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 astro- cyte heterogeneity is not new. Numerous anatomical distinctions have long been recognized among gray (pro- toplasmic) 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 recog- nition of an extended family of astroglial cells that share similarities with, but also exhibit differences to, proto- plasmic and ﬁbrous astrocytes, including Mu¨ller glia in the retina, Bergmann glia of the cerebellum, tanycytes at the base of the third ventricle, pituicytes in the neurohypoph- ysis, cribrosocytes at the optic nerve head, and others. These different cell types express various astrocyte-related molecules such as GFAP, S100b, 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,