Acta Neuropathol (2010) 119:7–35 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]. Roles in development 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 for- mation 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 devel- opment of white matter, the loss or dysfunction of astrocyte connexins and gap junctions leads to dysmelination [131]. Regulation of blood ﬂow 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]. Astro- cytes 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]. Fluid, ion, pH, and transmitter homeostasis 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 11 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 homeo- stasis 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 homeo- stasis 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 trans- mitters 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]. Roles in synapse function There is now steadily accumulating evidence that astro- cytes play direct roles in synaptic transmission through the regulated release of synaptically active molecules includ- ing glutamate, purines (ATP and adenosine), GABA, and D-serine [89, 162, 182, 215]. The release of such glio- transmitters occurs in response to changes in neuronal synaptic activity, involves astrocyte excitability as reﬂec- ted by increases in astrocyte [Ca??] , and can alter i neuronal excitability [89, 162, 182, 215]. Such evidence has given rise to the ‘tripartite synapse’ hypothesis, which posits that astrocytes play direct and interactive roles with neurons during synaptic activity in a manner that is essential for information processing by neural circuits [5, 89, 182]. In addition to having direct effects on synaptic activity via the release of gliotransmitters, astrocytes have the potential to exert powerful and long-term inﬂuences on synaptic function through the release of growth factors and related molecules. As discussed above, molecular mecha- nisms have been identiﬁed through which astrocytes play a role in the formation, maintenance, and pruning of syn- apses during development [15, 43, 230]. Such mechanisms may also provide astrocytes with the means of exerting powerful inﬂuences on synaptic remodeling and pruning in the healthy adult CNS or in response to CNS disorders [15]. Cytokines such as tumor necrosis alpha (TNFa) have been shown to inﬂuence homeostatic synaptic scaling by 123