Abstract
In astrocytes, as in other eukaryotic cells, vesicles have key cellular functions including constitutive housekeeping of the plasma membrane structure and cell-to-cell communication. On the one hand, vesicle traffic is associated with cell surface morphology exhibiting distinct glial microdomains. These determine the signaling potential and metabolic support for neighboring cells. On the other hand, vesicles are used in astrocytes for the release of vesicle-laden chemical messengers. This chapter addresses the properties of membrane-bound vesicles that store gliotransmitters (glutamate, adenosine 5’-triphosphate, peptides), other recycling vesicles, and endocytotic vesicles that are involved in the traffic of plasma membrane receptors such as the class II major histocompatibility molecules and membrane transporters (aquaporin 4 and excitatory amino acid transporter 2). Vesicle dynamics are also considered in view of diseases such as amyotrophic lateral sclerosis, multiple sclerosis, autistic disorders, trauma, edema, and states in which astrocytes contribute to neuroinflammation. In multiple sclerosis, for example, fingolimod, a recently introduced drug, apparently also affects vesicle traffic and gliotransmitter release from astrocytes, indicating that these processes may well be used as a target for the development of new therapies.
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Keywords
- Astrocyte
- Glia
- Vesicle
- Trafficking
- Reactive astrogliosis
- Morphology
- Gliotransmitter
- Antigen presentation
- Neuroinflammation
- Autism
- Amyotrophic lateral sclerosis
- Multiple sclerosis
3.1 Introduction
Astrocytes , the most abundant glial cells in the brain, have been considered subservient to neurons for almost a century. However, in the last two decades, experimental evidence has shown that astrocytes actively contribute to information processing in the central nervous system (CNS) . Many new functions have been described, including the regulation of synaptogenesis, synaptic transmission, brain microcirculation, roles in the formation and maintenance of the blood–brain barrier (BBB), contributions to the formation and resolution of brain edema , metabolic support for neurons, and participation in pathologic immune responses (Dong and Benveniste 2001; Haydon 2001; Ke et al. 2001; Anderson and Nedergaard 2003; De Keyser et al. 2003; Nedergaard et al. 2003; Zonta et al. 2003; Abbott et al. 2006; Gordon et al. 2007; Nase et al. 2008; Stevens 2008; Risher et al. 2009) . All these functions depend to a large extent on the mechanisms by which astrocytes communicate with the surrounding cells. These include plasma membrane channels, receptors, transporters, and mechanisms that mediate the exchange of molecules by exo- and endocytotic processes (Kreft et al. 2004; Osborne et al. 2009; Parpura and Zorec 2010; Guček et al. 2012; Parpura et al. 2012; Zorec et al. 2012). In exo- and endocytotic processes, signaling molecules are released from or are internalized into vesicles, respectively. In the cytoplasm, both exo- and endocytotic vesicles reach their cytoplasmic destination by trafficking , which involves the cytoskeleton (Potokar et al. 2005, 2007).
Membrane-bound vesicles in astrocytes carry several classes of molecules, such as amino acids, nucleotides, peptides, transporters , water channels, and receptors (Coco et al. 2003; Krzan et al. 2003; Bezzi et al. 2004; Pangrsic et al. 2007; Jean et al. 2008; Martineau et al. 2008; Parpura et al. 2010; Parpura and Zorec 2010; Vardjan et al. 2012; Martineau et al. 2013; Potokar et al. 2013a) . Their efficient delivery to the target destination in the cell is governed by vesicle mobility. It has been established recently that cytoplasmic vesicle mobility over distances of several micrometers is a tightly regulated process, involving cell signaling pathways and alterations in cytoskeleton dynamics. Under pathologic conditions (ischemia, trauma, edema, neuroinflammation) , different triggers alter vesicle mobility, as shown by several studies (Potokar et al. 2007, 2008, 2010, 2012, 2013a, 2013b; Stenovec et al. 2007, 2011; Trkov et al. 2012; Vardjan et al. 2012).
Single-vesicle trafficking studies in astrocytes have provided new insights into the roles of astrocytes in brain functioning. This review focuses on the mobility properties of exocytotic vesicles that transport gliotransmitters (glutamate, adenosine 5’-triphosphate [ATP], atrial natriuretic peptide [ANP], and brain-derived neurotrophic factor [BDNF]), membrane transporters (excitatory amino acid transporter 2 [EAAT2]; aquaporin 4 [AQP4]) and antigen-presenting receptors (major histocompatibility complex class II [MHC-II] receptors), and their role in health and disease. Although electron microscopy studies have revealed that astrocytes contain clear-core and, to a lesser extent, dense-core vesicles (Parpura and Zorec 2010) , it is currently unknown whether the trafficking of these is distinct, therefore the aim here is to highlight studies in which vesicle mobility was monitored in real time in astrocytes.
3.2 Key Pathophysiologic Considerations of Vesicle Dynamics: from Signaling to Morphology of Astrocytes
Neurologic diseases are considered to emerge when disruption of the homeostatic balance between neural cell damage, neuroprotection, and regeneration occurs. A key function of astrocytes is to provide homeostatic support in the brain, hence these cells are involved in every kind of neuropathology (Seifert et al. 2006; Giaume et al. 2007) . Moreover, these cells provide the first line of brain defense through regulation of the volume and composition of extracellular space (Kofuji and Newman 2004), such as extracellular levels of glutamate (Kirischuk et al. 2007). This function limits the excitotoxic burden of glutamate and is linked to the antioxidant system of astrocytes (Dringen 2000). However, astroglia may also contribute to neuronal damage through failure or reversal of various homeostatic cascades (Nedergaard and Dirnagl 2005; Giaume et al. 2007) . Pathologic insults to the CNS trigger a specific astrocytic reaction known as reactive astrogliosis , which aims to protect the brain parenchyma, isolate the damaged area, reconstruct the BBB, and promote remodeling of the neural circuitry through hypertrophic morphological changes in astrocytes (Wilhelmsson et al. 2006).
3.2.1 Altered Vesicle Dynamics
How can vesicles contribute to the pathologic potential of astrocytes? Although vesicles are involved in relatively rapid processes, such as in neuronal synaptic transmission, the response of regulated exocytosis in astrocytes is at least one or two orders of magnitude slower (Guček et al. 2012). Furthermore, there are even slower vesicle-based processes than astrocytic-regulated exocytosis. It has been estimated that the cell surface area is turned over by constitutive vesicle traffic in 5 to 6 h (Kreft and Zorec 1997). Hence, if such slow constitutive plasma membrane turnover occurs in astrocytes in vivo, only very slight imbalances in the rate of vesicle delivery to the plasma membrane relative to retrieval from the plasma membrane may, over relatively long periods of time, affect the properties of astrocytes and their responsiveness to physiologic and pathologic stimuli. For example, tissue remodeling in Alzheimer disease (AD), where Aβ protein can be internalized into the astrocytes (Nagele et al. 2003, 2004; Olabarria et al. 2010), likely involves altered vesicle dynamics, which may contribute to the progression of AD. Another example of impaired vesicle traffic may give rise to conditions such as intellectual deficiency (ID), formerly known as human mental retardation, a common disorder characterized by an IQ lower than 85. Poor cognitive ability can be the only visible sign in nonspecific ID, whereas behavioral deficits accompanied by other clinical signs may compose a syndrome (e.g., Down syndrome), or may be associated with metabolic, mitochondrial or developmental disorders (Luckasson and Reeve 2001). Symptoms appear early in life and affect between 2 and 3 % of the population. Family studies have demonstrated a relatively large number of X-linked forms of ID (XLID) with an incidence of about 0.9 to 1.4 in 1000 males (Turner 1996). One of the first genes discovered to be mutated in patients with XLID is GDI1 (D’Adamo et al. 1998). GDI1 encodes for αGDI, a protein physiologically involved in retrieving inactive GDP-bound Rab from the membrane. The identification of GDI1 as one of the genes causing human ID suggested that vesicular traffic in neuronal cells is an important pathway for development of cognitive functions (D’Adamo et al. 2002; Bianchi et al. 2009). Although the importance of αGDI in neuronal function has been demonstrated, it is unclear whether its role in glia vesicle trafficking contributes to the etiology of disease. αGDI protein regulates the function of Rab GTPases, such as Rab 4 and Rab 5, which have recently been shown to regulate the traffic of endosomes in astrocytes (Potokar et al. 2012), but it is likely that impaired vesicle traffic in astrocytes contributes to the ID.
3.2.2 Vesicles and Astrocyte Morphology
There are many mechanisms by which synaptic transmission is modulated by astrocytes, a partner of the tripartite synapse (Haydon 2001). These include morphological alterations of astrocytes. Because astrocytes ensheath synapses, local retractions or expansions of astrocytic processes, as observed by Theodosis et al. (2008), modify the geometry of the extracellular space, affecting neuron–glia interactions. Morphological changes in astrocytes also play an important role in pathologic states, since they become hypertrophic (Wilhelmsson et al. 2006). Astrocytes may swell and contribute to the development of brain edema and here vesicles carrying AQP4 seem important (Potokar et al. 2013a) as described below in Sect. 4.1.
What is the significance of morphological changes in astrocytes? The apposition of astrocyte membrane around the synaptic cleft seems, for example, to be an important determinant for the efficient removal of glutamate from the synaptic cleft, which determines the properties of synaptic signals (Marcaggi et al. 2003). Removal of glutamate from the synaptic cleft consists of coupled diffusion of glutamate in the synaptic cleft and flux into the astrocyte via plasma membrane glutamate transporters; glutamate then diffuses in the cytoplasm to sites where it is metabolized. Another example of coupled transport between the astrocyte and the synapse is the transport of metabolites, such as glucose and lactate . The flux of metabolites increases during activation of the synapse. Given that the volume of an astrocyte is much larger than that of the presynaptic terminal, where energy is consumed during synaptic activity (Harris et al. 2012), one has to consider that the metabolite transport intensities between the two compartments differ due to the different surface-to-volume ratios in relatively small and large objects (McMahon 1973). However, the volume of astrocytes is fragmented into smaller compartments. For example, Bergmann glial cells send specialized appendages that cover several synapses and form relatively independent compartments enwrapping synapses, termed glial microdomains (Grosche et al. 1999), through which glial cells interact with neurons (Grosche et al. 2002). Such volume fragmentation likely improves the disparity of the surface-to-volume ratio between the neuronal and astrocytic compartments. In Fig. 3.1, the volumes of the presynaptic terminal and the astrocytic process are considered similar. However, the volume of an astrocyte process is open via a passage to the bulk volume of an astrocyte through which metabolites are delivered and may also escape (Fig. 3.1). The transport intensity of molecules M within the volume of the astrocytic process (J 2 in Fig. 3.1) is considered to be much higher than that through the membrane facing the presynaptic terminal (J 1 in Fig. 3.1). To maintain a stable and sufficiently high concentration of the metabolite (M) in the astrocytic process, the fluxes have to be balanced. During synaptic activation, the rate of metabolite consumption in the synaptic compartment increases and this may lead to a decline in the concentration of the metabolite, unless a compensatory increase in metabolic influx occurs or reserves (e.g., glycogen) are activated. Whether such a process exists, however, remains to be investigated. Note that in Fig. 3.1, the transport capacity of molecule M between the compartments at rest likely favors that between the bulk volume of the astrocyte and the astrocytic process. However, the transport capacities may change if relative volumes of synaptic and astrocytic compartments are changed by putative regulatory processes. The narrower the passage connecting the astrocytic process to the bulk volume of the astrocyte, the smaller the potential loss of metabolites from the astrocytic process. An increase in the presynaptic terminal size was observed during functional inactivation of presynaptic terminals (Murthy et al. 2001). Changes in cell morphology have been observed during various active brain states (Shinohara et al. 2013). For example, in pathologic states such as trauma (Bardehle et al. 2013) and the late stages of AD (Verkhratsky et al. 2010), reactivated hypertrophic astrocytes (Wilhelmsson et al. 2006) are observed. Astrocyte atrophy was reported in some parts of the brain in the early stages of AD (Olabarria et al. 2010). These morphological cases likely mirror alterations in metabolic activity, whereby local fluxes of metabolites are corrected by morphological alterations due to altered neuron–glia interactions. However, the exact mechanisms of shape changes of astrocytes are unclear and are under active investigation by several laboratories.
One mechanism seems to involve G-protein coupled receptor (GPCR)-mediated processes. It has been known for some time that astroglial β-adrenergic receptors (β-ARs) functionally regulate astrocyte cellular morphology (Hatton et al. 1991). An increase in intracellular adenosine 3ʹ,5ʹ cyclic monophosphate (cAMP) production on β-AR stimulation induces astrocyte stellation (Fig. 3.2), i.e., transformation from a flattened polygonal morphology to a stellate process-bearing morphology (Shain et al. 1987; Bicknell et al. 1989). How vesicle traffic contributes to these processes is largely unclear. β-ARs are abundant on astrocytes in both white and grey matter of the brain (Aoki 1992; Sutin and Shao 1992; Zeinstra et al. 2000; Catus et al. 2011) and are likely involved in a number of pathologic conditions. It is likely that during the early stages of AD, when a reduction of noradrenaline was reported (Hammerschmidt et al. 2013), this may result in reduced cAMP signaling and in astrocyte atrophy, the latter as observed in the triple transgenic animal model of AD (Olabarria et al. 2010). Such astrocytic atrophy may lead secondarily to synaptic loss due to insufficient metabolic support of synapses by astrocytes. In this particular case, astrocytes signal to neighboring cells likely using gliotransmitter vesicles.
3.3 Gliotransmitter Vesicles
Gliotransmitters are chemicals released from glial cells and are synthesized by and/or stored in glia (Parpura and Zorec 2010) . Storage of gliotransmitters in membrane-bound vesicles as opposed to having them stored in the cytoplasm provides several advantages for cell-to-cell communication (Guček et al. 2012). In astrocytes , several types of gliotransmitter vesicles have been reported containing the amino acids glutamate and d-serine (Parpura et al. 1994; Bezzi et al. 2004; Kreft et al. 2004; Montana et al. 2004, 2006; Martineau et al. 2008, 2013), ATP (Coco et al. 2003; Pangrsic et al. 2007) , and peptides such as ANP (Krzan et al. 2003; Kreft et al. 2004), BDNF (Bergami et al. 2008), and tissue plasminogen activator (tPA) (Cassé et al. 2012). Several vesicle mobility experiments have been performed on primary cultured astrocytes to explore how vesicle mobility is altered under different physiologic and pathologic conditions.
It is not even a decade since the first spontaneous mobility of membrane-bound vesicles in astrocytes was described (Potokar et al. 2005), and subsequently confirmed (Crippa et al. 2006). To determine vesicle mobility, several parameters such as the total track length, the path a vesicle travels in a given period of time, the average velocity, the displacement, and the directionality index (ratio between the maximal displacement/total track length) can be measured. Maximal displacement represents a measure of the maximal net translocation of vesicles (Wacker et al. 1997). Consistent with other cell types (Burke et al. 1997; Tvaruskó et al. 1999; Duncan et al. 2003; Potokar et al. 2005), two distinct modes, directional and nondirectional, of vesicle mobility have been described in astrocytes, and these modes of mobility were able to switch while a vesicle was being observed (Potokar et al. 2005) (Fig. 3.3a) .
3.3.1 Amino Acid-loaded Vesicles
In astrocytes , glutamate is packaged into vesicles by the vesicular glutamate transporters (VGLUTs) VGLUT1, VGLUT2, and VGLUT3 (Danbolt 2001; Parpura and Zorec 2010) . Although the existence of VGLUT1 in mouse astrocytes has been questioned (Li et al. 2013), VGLUT1-containing vesicles in rat astrocytes are small and electron lucent, with an estimated diameter of ~ 30 nm in situ (Bezzi et al. 2004) and ~ 50 nm when they recycle (Stenovec et al. 2007), but larger sizes have also been reported (Chen et al. 2005; Malarkey and Parpura 2011). Why different vesicle diameters have been reported for glutamatergic vesicles is not known but this may also be associated with different microscopy techniques used by different investigators. Figure 3.4 shows an example of vesicles fluorescently labeled by d-serine antibodies in fixed cultured astrocytes examined by confocal and stimulation emission depletion microscopy (STED, a superresolution fluorescence microscopy technique (Hell and Wichmann 1994; Jorgacevski et al. 2011)) that presents new possibilities to resolve the question of the different diameters reported for gliotransmitter vesicles in astrocytes.
In addition to studies of spontaneous vesicle mobility, experiments on astrocytes have revealed that vesicle mobility may be altered in stimulated cells. This was observed when glutamatergic vesicles were labeled in vivo using a novel approach (Stenovec et al. 2007) based on the fact that after Ca2+-dependent exocytosis (Parpura et al. 1995; Jeftinija et al. 1996; Zhang et al. 2004a, b), exocytotic vesicles are endocytosed (Stenovec et al. 2007). Before entering the endocytotic pathway, exocytotic vesicles may enter several rounds of recycling, whereby the transient exocytotic fusion pore reopens several times. Vesicles that transiently expose their lumen to the extracellular space may take up fluorescently labeled antibodies against VGLUT1. These antibodies were raised against the amino acid residues that were thought to be present only in the cytoplasmic part of VGLUT1 transporter protein, but these are likely also present in the vesicle lumen in native vesicles, because anti-VGLUT1 antibodies label the luminal part of vesicles (Almqvist et al. 2007; Stenovec et al. 2007). At higher intracellular concentrations of Ca2+ ([Ca2+]i) induced by4 µM ionomycin or 1 mM ATP, immunolabeling was more pronounced and the directional mobility of VGLUT1 vesicles was increased. Together with directionality, the fraction of fast-moving vesicles (> 0.05 μm/s) increased at higher [Ca2+]i. These effects were absent in the cells preloaded with high-affinity Ca2+ buffer (BAPTA-AM). Microtubules, actin, and vimentin filaments likely play a role in the mobility process of VGLUT1 vesicles, because the disruption of actin attenuated their mobility (Stenovec et al. 2007). As discussed by Stenovec et al. (2007), regulation of vesicle mobility after vesicle retrieval may be involved in various aspects of physiology, such as synaptic plasticity (Aravanis et al. 2003), silent synapses (Gasparini et al. 2000), astrocyte-to-neuron communication (Haydon 2001; Volterra and Meldolesi 2005), and possibly more widely in cell biology in the genesis and removal of vesicles from the plasma membrane (Pelkmans and Zerial 2005). The stimulation-enhanced mobility of glutamatergic vesicles contrasts the stimulation-induced attenuation of mobility of peptidergic vesicles and endosomal structures, which likely plays an important role under pathologic conditions (Potokar et al. 2008, 2010, 2011).
3.3.2 ATP-loaded Vesicles
ATP, an essential component of long-range Ca2+ signaling in the nervous system (Zimmermann 1994), is also an important astrocytic gliotransmitter (Parpura and Zorec 2010) and one of the major extracellular messengers for interastrocyte Ca2+-mediated communication (Guthrie et al. 1999; Wang et al. 2000) . In addition to nonvesicular modes of ATP release, such as the release of ATP from astrocytes mediated by the connexin hemichannel (Stout et al. 2002; Stehberg et al. 2012), volume-sensitive organic osmolyte and anion channels (Blum et al. 2010), Ca2+-dependent exocytotic ATP release from astrocytes has also been confirmed (Parpura and Zorec 2010). ATP-loaded astrocytic vesicles seem to be heterogeneous. So far in astrocytes, the vesicular distribution of ATP has been shown to overlap with the marker of dense-core granules in the hippocampus, secretogranin II (Calegari et al. 1999; Coco et al. 2003) and in lysosomes (Jaiswal et al. 2007; Zhang et al., 2007; Li et al. 2008; Verderio et al. 2012). ATP seems to be co-stored together with classic neurotransmitters (acetylcholine in neurons and noradrenaline in neurons and chromaffin cells) (Zimmermann 1994) or with peptides (Calegari et al. 1999; Belai and Burnstock 2000; Bodin and Burnstock 2001; Coco et al. 2003; Pangrsic et al. 2007). In neonatal cortical rat astrocytes, ATP-containing vesicles seem to substantially co-store ANP (39 ± 7 %) (Pangrsic et al. 2007). Under spontaneous conditions, most of the ATP vesicles were located in close proximity to the plasma membrane (up to 150 nm) and this coincided with the observation that quinacrine-loaded vesicles displayed mainly nondirectional spontaneous mobility and only 4 % of vesicles were highly mobile (directional mobility). High [Ca2+]i affected both types of vesicle mobility and completely abolished directional mobility. After a triggered increase in [Ca2+]i, less ATP vesicles were observed in the cells, likely due to Ca2+-activated discharge of the fluorescent/quinacrine cargo by regulated exocytosis. This effect was obstructed by the presence of the dominant-negative soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) domain peptide, which interferes with the formation of the SNARE complex (Zhang et al. 2004b; Pangrsic et al. 2007).
ATP is considered to be a major gliotransmitter in the propagation of calcium waves among astrocytes (Haydon 2001), and in the modulation of neuronal activity (Zhang et al. 2003; Pascual et al. 2005; Haydon and Carmignoto 2006) , the exocytotic release of ATP may play a role in the delivery of this gliotransmitter to the extracellular milieu as a signaling messenger for intercellular communication. In the dominant-negative SNARE mouse model, it was shown that ATP release is reduced and this prevents tissue damage after a stroke (Hines and Haydon 2013).
3.3.3 Peptide-loaded Vesicles
ANP, which is stored in membrane-bound vesicles, was first shown to be released by Ca2+-dependent exocytosis from astrocytes (Krzan et al. 2003). The cytoplasmic mobility in the secretory pathway was monitored using ANP.emd fluorescent recombinant protein (Han et al. 1999), whereas the mobility in the recycling pathway was monitored using an immunolabeling approach in living cells (Potokar et al. 2008).
The major difference between the mobility of ANP vesicles monitored in the different pathways in rat astrocytes was the traveling speed. In vesicles traveling from the cytoplasm to the plasma membrane, the speed was 0.4 ± 0.007 µm/s (nondirectional vesicles 0.3 ± 0.005 µm/s, directional vesicles 0.5 ± 0.01 µm/s), indicating that all vesicles were mobile but some displayed directional motion. Such rapid vesicle mobility is comparable with the directional movement of vesicles in some neurons (Potokar et al. 2005). However, their mobility was significantly attenuated after depolymerization of microtubules, actin filaments, and intermediate filaments (IFs) to 0.30 ± 0.0003 µm/s, 0.08 ± 0.01 µm/s and 0.21 ± 0.01 µm/s, respectively (Potokar et al. 2007). In mouse astrocytes, the measured parameters of mobility were lower compared with rat astrocytes (Potokar et al. 2013b). The slight difference in speed was also recorded between wild-type (WT) astrocytes and astrocytes without IFs, and the extent of directional mobility was also lower in astrocytes without IFs (Potokar et al. 2007). These data support the hypothesis that IFs are required for long-range directional vesicle mobility by acting as three-dimensional conduits. The importance of astrocytic IFs in vesicle mobility under pathologic conditions has also been confirmed by more recent studies (Vardjan et al. 2012).
The mobility of ANP vesicles in the recycling pathway has been monitored in rat astrocytes. Vesicle recycling has been considered for secretory granules, which are released by stimulated exocytosis (Taraska et al. 2003). During this process, the granule remains intact, except for the loss of the contents and some of the membrane proteins. Recycling occurs when the fusion pore is rapidly resealed in the exocytotic process and the vesicle is retrieved into the cytoplasm without intermixing of membranes and without collapse of the vesicle membrane into the surface membrane (Jahn and Südhof 1999; Valtorta et al. 2001; Taraska et al. 2003). When studying recycling ANP vesicles, they exhibited one order of magnitude slower mobility than secretory ANP vesicles (Potokar et al. 2013b). What is the physiologic significance of these results? The mobility of vesicles retrieved from the plasma membrane after exocytotic fusion is likely related to the efficiency of vesicle cargo discharge. If sufficient time is allowed (during attenuated vesicle mobility), the vesicle cargo can be completely discharged from the vesicle lumen, especially if peptides in the vesicle are aggregated into dense matrices (detected as electron-dense material on electron microscopy) and their discharge is inefficient unless the vesicles exhibit a fusion pore that permits prolonged discharge of the vesicle cargo. Furthermore, brain ANP content is significantly increased after experimental brain infarction, but not after brain hemorrhage, after contusion and in controls, indicating that ANP-positive astrocytes may increase in number and may be involved in the regulation of the cerebral blood flow in the infarcted brain area (Nogami et al. 2001). The altered cerebral blood flow thus also underlies enhanced delivery of ANP vesicles to the plasma membrane and/or release of ANP from astrocytic vesicles.
In addition, a specialized form of bidirectional communication involving signaling peptides exists between neurons and astroglia . BDNF secreted from neurons in its precursor form (pro-BDNF) is cleared from the extracellular space into nearby astrocytes, which internalize it via formation of a complex with the pan-neurotrophin receptor p75 and subsequent clathrin-dependent endocytosis. Endocytosed pro-BDNF is then routed into a fast recycling pathway for subsequent SNARE-dependent secretion triggered by glutamate (Bergami et al. 2008). Similarly, tPA appears as an element of the crosstalk between neurons and astrocytes. tPA released by neurons is constitutively endocytosed by astrocytes via the low-density lipoprotein-related protein receptor, and is then exocytosed in a regulated manner. Here, however, the exocytotic recycling of tPA by astrocytes is inhibited by extracellular glutamate. Kainate receptors of astrocytes act as sensors of extracellular glutamate and, via a signaling pathway involving protein kinase C, modulate the exocytosis of tPA (Cassé et al. 2012). Apart from this, BDNF is the most prevalent growth factor in the CNS and is widely implicated in psychiatric diseases , such as major depressive disorder (MDD), schizophrenia, addiction, and Rett syndrome (Autry et al. 2011). Notably, N-methyl-d-aspartate receptor (NMDAR) antagonists may produce fast-acting behavioral antidepressant effects in patients with depression and studies in mouse models indicate that these effects depend on the rapid synthesis of BDNF. At the cellular level, the blockade of NMDAR deactivates eukaryotic elongation factor 2 (eEF2) kinase/CaMKIII, resulting in reduced eEF2 phosphorylation and de-suppression of translation of BDNF (Autry et al. 2011). Although the regulation of protein synthesis has been identified as a valuable therapeutic target in the treatment of MDD, one cannot rule out the possibility that fast-acting antidepressants affect trafficking and/or release of presynthesized BDNF from brain cells; patients with depression report alleviation of MDD symptoms within 2 h of a single, low-dose, intravenous infusion of the antidepressant drug (Zarate et al. 2006).
Whether vesicles in intact tissue exhibit similar mobility to cultured cells was tested by labeling recycling vesicles in astrocytes in hippocampal tissue slices, because brain tissue slices represent a preparation that is physiologically closer to that occurring in vivo, i.e. cell-to-cell contacts and tissue architecture are preserved as present in the brain (Potokar et al. 2009). We incubated brain slices from mice with antibodies either against ANP or against VGLUT1. Vesicles in astrocytes from the CA1 region of the hippocampus were recorded. The recording of vesicle mobility was performed with two-photon microscopy. The fluorescent puncta exhibited two types of mobility: nondirectional and directional. The average velocity of ANP-containing granules in slices from mice was approximately 0.04 µm/s, which is similar to that reported for recycling ANP granules in rat primary astrocyte cultures (0.06 µm/s) (Potokar et al. 2008), but one order of magnitude slower than the velocity of pro-ANP.emd-labeled granules (Potokar et al. 2005, 2007), where the average velocity was 0.4 µm/s. The mobility of VGLUT1 vesicles was analyzed similarly. The VGLUT1 vesicles in the slices were slightly slower than the ANP vesicles; their average velocity was approximately 0.03 µm/s. The velocity of recycling VGLUT1 vesicles in the slices was also slightly slower than recycling VGLUT1 vesicles from rat primary astrocyte cultures (0.05 µm/s) (Stenovec et al. 2007). Although vesicle mobility may differ in different brain regions, these results show that the experimental data obtained from cultured astrocytes closely resemble the properties of vesicle mobility observed in tissue slices.
3.4 Other Vesicles
The mobility properties of endosomes and lysosomes have been described in detail in mouse (Potokar et al. 2010) and rat astrocytes (Stenovec et al. 2011). These vesicles were labeled by LysoTracker dye (Ly) and exhibited slow mobility compared with other vesicle types (Potokar et al. 2013b). The direction and speed of Ly vesicles was shown to be influenced by the absence of astrocytic IFs. The trafficking of Ly-labeled vesicles seems to be regulated differently from glutamate-containing (VGLUT1-positive) and peptide-containing (ANP-positive) vesicles under different physiologic conditions. Cell stimulation to trigger an increase in [Ca2+]i significantly reduced the mobility of Ly-labeled vesicles in WT astrocytes but not in astrocytes devoid of IFs (GFAP −/− Vim −/− astrocytes) (Pekny et al. 1998; Eliasson et al. 1999; Wilhelmsson et al. 2004) . Moreover, stimulation-dependent regulation of VGLUT1- and ANP-positive vesicles was attenuated by the absence of IFs. Because these filaments get overexpressed under pathologic conditions (Eliasson et al. 1999), it is likely that the traffic of distinct vesicle types is altered under these conditions (Potokar et al. 2010), likely leading to vesicle traffic jams (Potokar et al. 2011).
The regulation of endosome and lysosome mobility may exhibit completely different properties in pathophysiologic states. For example, if purified IgG antibodies harvested from patients with sporadic amyotrophic lateral sclerosis (ALS) are applied to astrocytes, the mobility of Ly-labeled compartment(s) is transiently increased, likely in a Ca2+-dependent manner, indicating that acidic compartments may not represent a functionally homogeneous subcellular compartment, although endosomes and lysosomes were stained predominantly (Stenovec et al. 2011). The altered mobility is likely associated with altered Ca2+ homeostasis by ALS IgGs (Milošević et al. 2013). How do these results relate to the disease? ALS is a complex, incurable, and non-cell autonomous degenerative disease that affects upper and lower motor neurons located in a neighborhood enriched with nonneuronal cells; it occurs in adulthood (Haidet-Phillips et al. 2011) with a projected lifetime risk of 1 in 2000 (Eisen 2009). The hallmark of ALS is selective death of motor neurons, although glial cells are also affected. In ALS, astrocytic function is compromised in several ways that impair neuronal survival and includes deficient release of (i) neurotrophic factors (Ekestern 2004); (ii) release of nerve growth factor or extracellular mutant superoxide dismutase 1 (SOD1) (Pehar et al. 2004; Urushitani et al. 2006); (iii) insufficient clearance of glutamate from the synaptic cleft, due to reduced density and loss of EAAT2 (Rothstein et al. 1995). Disturbance of the physiologic balance between neurons and astrocytes may therefore play a key role in motor neuron degeneration in ALS (Van Damme et al. 2005). In addition, activation of a systemic immune response in patients with ALS (Zhang et al. 2005) may play a role in the continuing pathology of ALS, once the BBB is compromised (Garbuzova-Davis et al. 2007). Correspondingly, motor neurons survived less when cocultured on astrocytes expressing the mutant form of Cu-Zn SOD1, as in the familial type of ALS, than on WT astrocytes (Di Giorgio et al. 2007). The application of conditioned medium from mutant SOD1-expressing astrocytes decreased the survival of motor neurons, suggesting the presence of astrocyte-secreting molecules that kill neurons (Nagai et al. 2007). Alterations in vesicle dynamics may thus reflect changes associated with the progression of the disease and may offer possibilities for the development of new diagnostic tests.
3.4.1 Aquaporin Transporting Vesicles
Recently, it was shown that the water channel AQP4 is also trafficking in vesicles that exhibit the properties of endosomes and lysosomes (Potokar et al. 2013a). This key molecule is involved in brain water homeostasis and is one of the three AQPs identified in brain cells in vitro and in vivo (Hasegawa et al. 1994; Jung et al. 1994; Nielsen et al. 1997; Badaut et al. 2002; Amiry-Moghaddam and Ottersen 2003). AQP4 isoforms in rodent and nonhuman primate brains are the most strongly expressed in astrocytic end feet surrounding the BBB (Nielsen et al. 1997; Nagelhus et al. 1998; Neely et al. 1999; Arciénega et al. 2010) and have also been identified in astrocytic processes in contact with synapses (Nielsen et al. 1997; Badaut et al. 2000a, b). Several studies have suggested an important role of AQP4 in water transport in several processes including astrocyte swelling and brain edema formation/resolution under various pathologic conditions, both in vitro (Yamamoto et al. 2001; Arima et al. 2003) and in vivo (Manley et al. 2000; Ke et al. 2001; Papadopoulos et al. 2004). Water transport through the cell membrane may be regulated by the permeability properties of AQP4 (Gunnarson et al. 2008; Nicchia et al. 2011), the heterogeneity of AQP4 crystalline-like orthogonal arrays of particles (Hirt et al. 2011), and, as recently suggested, by the mobility of the AQP4 vesicles that are delivered to and from the plasma membrane (Potokar et al. 2013a). The properties of AQP4 vesicle mobility are described in a study by Potokar et al. (2013a). AQP4 is one of the newly described basic AQP4 isoforms (Moe et al. 2008). In unstimulated conditions, the mobility of AQP4 vesicles resembled the mobility of slow recycling and endosomal vesicles (Stenovec et al. 2007; Potokar et al. 2008, 2010). After dibutyryl-cAMP treatment, a model to induce reactive astrocytosis, an increased AQP4 signal was measured at the plasma membrane after 15 min (and remained increased even after 24 h) and the mobility of AQP4 vesicles was affected (Potokar et al. 2013a). These data indicate that the regulation of vesicle mobility in the relatively short time scale is an important regulatory mechanism to alter the delivery and removal ratio of AQP4 vesicles at the plasma membrane in reactive astrocytes. Decreased mobility with significantly lower directionality might contribute to restraining the AQP4 vesicles near the plasma membrane and may also be linked to dibutyryl-cAMP-induced rearrangements of the F-actin cytoskeleton mesh already considered to be one of the major factors responsible for increased AQP4 plasma membrane localization (Nicchia et al. 2008).
During the early stages of brain edema formation, astrocytes swell (Papadopoulos et al. 2004; Nase et al. 2008; Risher et al. 2009). A reduction in osmolarity triggers an increase in soma volume; this has been measured in tissue and in cultured rat astrocytes (Takano et al. 2005; Pangrsic et al. 2006; Thrane et al. 2011). The increase in cell volume may be accompanied by an increased rate of insertion of exocytotic vesicles in the membrane (Pasantes-Morales et al. 2002). Potokar et al. (2013a) reported that hypoosmotic conditions affected plasma membrane localization of AQP4 in rat astrocytes, in particular hypoosmotic stimulation triggered a transient increase in AQP4 plasma membrane localization. These changes were related to changes in AQP4 vesicle traffic; an increase in AQP4 plasma membrane localization overlapped with the observed decrease in mobility of AQP4 vesicles and the subsequent decrease in AQP4 plasma membrane localization overlapped with increased AQP4 vesicle mobility. The changes in mobility occurred predominantly in directional vesicles. These studies have shown that vesicle dynamics are playing a role in the cell swelling response at least by regulating the density of AQP4 channels in the plasma membrane. Whether cell swelling can be affected by manipulating vesicle traffic remains to be studied in the future.
3.4.2 Vesicles Delivering Plasma Membrane MHC Receptors and Transporters
Intracellular traffic of astrocytic vesicles, including endosomes and lysosomes, may also serve to deliver plasma membrane-associated MHC receptors (Soos et al. 1998; Vardjan et al. 2012) and transporters, such as glutamate transporter EAAT2 (Stenovec et al. 2008) where the nature of vesicles is not clear.
On exposure to the proinflammatory cytokine, interferon-γ (IFN-γ), otherwise immunologically silent astrocytes may begin to express MHC-II molecules and antigens on their surface and act as nonprofessional antigen-presenting cells (APCs). It has been suggested that IFN-γ-activated astrocytes participate in antigen presentation and activation of CD4 helper T cells in immune-mediated disorders of the CNS including multiple sclerosis (Fontana et al. 1984; Soos et al. 1998) and experimental autoimmune encephalomyelitis (Shrikant and Benveniste 1996).
In general, the delivery of MHC-II molecules from MHC-II compartments to the cell surface of APCs is mediated via a cytoskeletal network and is most likely completed with the fusion of MHC-II-carrying late endosomes/lysosomes with the plasma membrane. Actin microfilaments (Barois et al. 1998), microtubules (Wubbolts et al. 1999; Vyas et al. 2007), and their motor proteins (Wubbolts et al. 1999; Vascotto et al. 2007) have been shown to mediate trafficking of MHC-II compartments in APCs. Only recently, the role of IFs in MHC-II trafficking was investigated in IFN-γ-activated astrocytes (Vardjan et al. 2012), which as reactive astrocytes overexpress IFs (Junyent et al. 2011).
IFN-γ was shown to induce expression of MHC-II molecules on the astrocytic plasma membrane and late endosomes/lysosomes (Vardjan et al. 2012). The latter can be specifically labeled with Alexa Fluor® 546-conjugated dextran (Fig. 3.5a) (Jaiswal et al. 2002; Gabrijel et al. 2008; Vardjan et al. 2012). Time-lapse confocal imaging and fluorescent dextran labeling of late endosomes/lysosomes in WT astrocytes and in astrocytes devoid of IFs (GFAP −/− Vim −/−) revealed faster and more directional movement of late endosomes/lysosomes in IFN-γ-treated astrocytes than in untreated astrocytes (Potokar et al. 2013b). However, vesicle mobility was lower and less directional in IFN-γ-treated IF-deficient astrocytes than in WT astrocytes (Fig. 3.5b, c), indicating that the IFN-γ-induced increase in the mobility of MHC-II-carrying late endosomes/lysosomes is IF dependent. Application of ATP and the subsequent increase in [Ca2+]i induced attenuation of the mobility of late endosomes/lysosomes was more apparent in the presence of IFs (Fig. 3.5b, c), implying a role for IFs in this process.
These data indicate that, in IFN-γ-activated astrocytes, upregulation of IFs allows faster and therefore more efficient delivery of MHC-II molecules to the cell surface. Reduced mobility of late endosomes/lysosomes due to increase in [Ca2+]i may increase their probability of docking and fusion (Potokar et al. 2010), which, in astrocytes acting as APCs, may serve as an additional regulatory mechanism that controls the onset of late endosomal/lysosomal fusion and final delivery of MHC-II molecules to the cell surface (Vardjan et al. 2012). Besides IFN-γ, endogenous suppressors, including norepinephrine, have been shown to regulate the expression of MHC-II molecules in astrocytes (Frohman et al. 1988; De Keyser et al. 2004) . The effects of norepinephrine are mediated through activation of G-protein-coupled β-ARs on astrocytes and subsequent activation of the cAMP signaling pathway. Our recent unpublished data suggest that the mobility and fusion of late endosomes/lysosomes involved in antigen presentation are also affected by activation of astrocytic β-ARs. Although these studies were carried out in vitro, all these regulatory mechanisms may enable antigen-presenting reactive astrocytes in vivo to respond rapidly and in a controlled manner during CNS inflammation.
Astrocytes play a key role in the uptake of glutamate , which is released into the extracellular space from glutamatergic neurons during synaptic transmission (Vesce et al. 1999; Amara and Fontana 2002) and from astrocytes themselves (Parpura et al. 1994). Physiologically, glutamate is cleared from the synaptic cleft via plasmalemma glial glutamate transporters GLAST (EAAT1) and GLT1 (EAAT2) (Danbolt 2001); its uptake is driven by the electrochemical gradient of sodium (O’Kane et al. 1999). The flux of transported molecules also depends on the density of transporters in the cell plasma membrane (Robinson 2002; Huang and Bergles 2004), which determines whether synaptic independence is compromised by the synaptic transmitter crosstalk. The density of EAAT2 in astrocyte plasma membrane is regulated by exo-/endocytosis in a Ca2+-dependent manner (Stenovec et al. 2008). The altered trafficking of EAAT2 to/from the plasma membrane may result in diminished net uptake of extracellular glutamate, and an overabundance of glutamate accompanied by failure of astrocytes to remove it may lead to neuronal excitotoxicity resulting in a selective loss of motor neurons as in ALS. Therefore, it may be useful to modify vesicle dynamics by drugs in order to minimize the adverse conditions associated with such a cell process.
3.5 Do Drugs Target Vesicle Dynamics in Astrocytes?
With advances in the understanding of the nature of vesicle mobility in astrocytes, a question has emerged whether there are any drugs that affect vesicle dynamics and could be used to treat neurologic diseases. Although the experimental evidence has revealed that different types of vesicles exhibit specific properties, it is possible that, under pathologic conditions, these may change. These include altered vesicle dynamics, changes in molecules that are released by vesicular mechanisms, alterations in the plasma membrane surface signaling landscape (altered densities of transporters, receptors, and associated signaling mechanisms) and changes in vesicle dynamics associated with morphology of astrocytes. All these factors may contribute to changes in communication between astrocytes and neighboring cells. However, one may consider that the least change may occur, if vesicle dynamics are attenuated, which may contribute to the minimization of vesicle-mediated changes in the cell. In line with this is the discovery that vesicle mobility was attenuated by fingolimod or FTY720 (Trkov et al. 2012). This drug was recently introduced as a therapeutic for the treatment of multiple sclerosis (Chun and Brinkmann 2011). It was shown that FTY720 accumulates in tissue hydrophobic pools (Foster et al. 2007), such as the white matter in the CNS, where it can reach concentrations that affect astrocytic vesicle mobility and consequently their ability to participate in regulated exocytosis (Trkov et al. 2012). This action may be part of its therapeutic effectiveness in patients with multiple sclerosis. The mechanism of reduction of vesicle mobility by fingolimod likely involves fingolimod-induced changes in [Ca2+]i homeostasis. Figure 3.6 shows that the application of fingolimod augments [Ca2+]i measured by the Fluo 4 fluorescent Ca2+ dye. In Fig. 3.6e, the time course of increased [Ca2+]i is shown for 5 individual astrocytes. These increases in [Ca2+]i are associated with the reduced mobility of peptidergic vesicles depicted in Fig. 3.6b–d. However, vesicle types other than peptidergic vesicles were also shown to be sensitive to fingolimod (Trkov et al. 2012). Moreover, astrocytes were considered to be the major source of a number of other molecules, including eicosanoids (prostaglandins, prostacyclins, thromboxanes, and leukotrienes) and these proinflammatory signaling molecules in the CNS are released via an ATP-dependent mechanism (Murphy et al. 1988). In astrocytes, ATP itself is released via regulated exocytosis, which participates in the neuroinflammatory and other pathologic states in the CNS. Thus, new therapeutics, such as FTY720 (Trkov et al. 2012), that affect vesicle mobility represent a novel possibility for the development of new therapeutics for neurologic diseases.
3.6 Future Perspectives
Vesicle dynamics in astrocytes are altered in pathologic states. Although studied less intensely, vesicle dynamics may also contribute to shape changes in astrocytes. These occur under physiologic conditions and when astrocytes swell or become hypertrophic or atrophic, which occurs in several disease states. Second messenger cAMP, which is involved in shape changes in astrocytes, also plays an important role in regulating glucose metabolism (Prebil et al. 2011b). It will be important to understand how energy support is regulated in view of vesicle dynamics and the morphological changes that take place in astrocytes in health and disease. Therefore, metabolic coupling measurements of d-glucose (Prebil et al. 2011a) and other metabolites, second messengers and measurements of shape changes will help us to understand the spatiotemporal coupling and interactions between neurons and glia.
References
Abbott N, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53
Almqvist J, Huang Y, Laaksonen A, Wang D, Hovmöller S (2007) Docking and homology modeling explain inhibition of the human vesicular glutamate transporters. Protein Sci 16:1819–1829
Amara SG, Fontana AC (2002) Excitatory amino acid transporters: keeping up with glutamate. Neurochem Int 41:313–318
Amiry-Moghaddam M, Ottersen OP (2003) The molecular basis of water transport in the brain. Nat Rev Neurosci 4:991–1001
Anderson C, Nedergaard M (2003) Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci 26:340–344; author reply 344–345
Aoki C (1992) Beta-adrenergic receptors: astrocytic localization in the adult visual cortex and their relation to catecholamine axon terminals as revealed by electron microscopic immunocytochemistry. J Neurosci 12:781–792
Aravanis AM, Pyle JL, Tsien RW (2003) Single synaptic vesicles fusing transiently and successively without loss of identity. Nature 423:643–647
Arciénega II, Brunet JF, Bloch J, Badaut J (2010) Cell locations for AQP1, AQP4 and 9 in the non-human primate brain. Neuroscience 167:1103–1114
Arima H, Yamamoto N, Sobue K, Umenishi F, Tada T, Katsuya H, Asai K (2003) Hyperosmolar mannitol simulates expression of aquaporins 4 and 9 through a p38 mitogen-activated protein kinase-dependent pathway in rat astrocytes. J Biol Chem 278:44525–44534
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475:91–95
Badaut J, Verbavatz JM, Freund-Mercier MJ, Lasbennes F (2000a) Presence of aquaporin-4 and muscarinic receptors in astrocytes and ependymal cells in rat brain: a clue to a common function? Neurosci Lett 292:75–78
Badaut J, Nehlig A, Verbavatz J, Stoeckel M, Freund-Mercier MJ, Lasbennes F (2000b) Hypervascularization in the magnocellular nuclei of the rat hypothalamus: relationship with the distribution of aquaporin-4 and markers of energy metabolism. J Neuroendocrinol 12:960–969
Badaut J, Lasbennes F, Magistretti PJ, Regli L (2002) Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab 22:367–378
Bardehle S, Krüger M, Buggenthin F, Schwausch J, Ninkovic J, Clevers H, Snippert HJ, Theis FJ, Meyer-Luehmann M, Bechmann I, Dimou L, Götz M (2013) Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nat Neurosci 16:580–586
Barois N, Forquet F, Davoust J (1998) Actin microfilaments control the MHC class II antigen presentation pathway in B cells. J Cell Sci 111(Pt 13):1791–1800
Belai A, Burnstock G (2000) Pattern of distribution and co-localization of NOS and ATP in the myenteric plexus of human fetal stomach and intestine. Neuroreport 11:5–8
Bergami M, Santi S, Formaggio E, Cagnoli C, Verderio C, Blum R, Berninger B, Matteoli M, Canossa M (2008) Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes. J Cell Biol 183:213–221
Bezzi P, Gundersen V, Galbete J, Seifert G, Steinhäuser C, Pilati E, Volterra A (2004) Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 7:613–620
Bianchi V, Farisello P, Baldelli P, Meskenaite V, Milanese M, Vecellio M, Muhlemann S, Lipp HP, Bonanno G, Benfenati F, Toniolo D, D’Adamo P (2009) Cognitive impairment in Gdi1-deficient mice is associated with altered synaptic vesicle pools and short-term synaptic plasticity, and can be corrected by appropriate learning training. Hum Mol Genet 18:105–117
Bicknell RJ, Luckman SM, Inenaga K, Mason WT, Hatton GI (1989) Beta-adrenergic and opioid receptors on pituicytes cultured from adult rat neurohypophysis: regulation of cell morphology. Brain Res Bull 22:379–388
Blum AE, Walsh BC, Dubyak GR (2010) Extracellular osmolarity modulates G protein-coupled receptor-dependent ATP release from 1321N1 astrocytoma cells. Am J Physiol Cell Physiol 298:C386–C396
Bodin P, Burnstock G (2001) Evidence that release of adenosine triphosphate from endothelial cells during increased shear stress is vesicular. J Cardiovasc Pharmacol 38:900–908
Burke N, Han W, Li D, Takimoto K, Watkins S, Levitan E (1997) Neuronal peptide release is limited by secretory granule mobility. Neuron 19:1095–1102
Calegari F, Coco S, Taverna E, Bassetti M, Verderio C, Corradi N, Matteoli M, Rosa P (1999) A regulated secretory pathway in cultured hippocampal astrocytes. J Biol Chem 274:22539–22547
Cassé F, Bardou I, Danglot L, Briens A, Montagne A, Parcq J, Alahari A, Galli T, Vivien D, Docagne F (2012) Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals. J Neurosci 32:5186–5199
Catus SL, Gibbs ME, Sato M, Summers RJ, Hutchinson DS (2011) Role of β-adrenoceptors in glucose uptake in astrocytes using β-adrenoceptor knockout mice. Br J Pharmacol 162:1700–1715
Chen X, Wang L, Zhou Y, Zheng LH, Zhou Z (2005) “Kiss-and-run” glutamate secretion in cultured and freshly isolated rat hippocampal astrocytes. J Neurosci 25:9236–9243
Chun J, Brinkmann V (2011) A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov Med 12:213–228
Coco S, Calegari F, Pravettoni E, Pozzi D, Taverna E, Rosa P, Matteoli M, Verderio C (2003) Storage and release of ATP from astrocytes in culture. J Biol Chem 278:1354–1362
Crippa D, Schenk U, Francolini M, Rosa P, Verderio C, Zonta M, Pozzan T, Matteoli M, Carmignoto G (2006) Synaptobrevin2-expressing vesicles in rat astrocytes: insights into molecular characterization, dynamics and exocytosis. J Physiol 570:567–582
D’Adamo P, Menegon A, Lo Nigro C, Grasso M, Gulisano M, Tamanini F, Bienvenu T, Gedeon AK, Oostra B, Wu SK, Tandon A, Valtorta F, Balch WE, Chelly J, Toniolo D (1998) Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nat Genet 19:134–139
D’Adamo P, Welzl H, Papadimitriou S, Raffaele di Barletta M, Tiveron C, Tatangelo L, Pozzi L, Chapman PF, Knevett SG, Ramsay MF, Valtorta F, Leoni C, Menegon A, Wolfer DP, Lipp HP, Toniolo D (2002) Deletion of the mental retardation gene Gdi1 impairs associative memory and alters social behavior in mice. Hum Mol Genet 11:2567–2580
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105
De Keyser J, Zeinstra E, Frohman E (2003) Are astrocytes central players in the pathophysiology of multiple sclerosis? Arch Neurol 60:132–136
De Keyser J, Zeinstra E, Mostert J, Wilczak N (2004) Beta 2-adrenoceptor involvement in inflammatory demyelination and axonal degeneration in multiple sclerosis. Trends Pharmacol Sci 25:67–71
Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10:608–614
Dong Y, Benveniste E (2001) Immune function of astrocytes. Glia 36:180–190
Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62:649–671
Duncan R, Greaves J, Wiegand U, Matskevich I, Bodammer G, Apps D, Shipston M, Chow R (2003) Functional and spatial segregation of secretory vesicle pools according to vesicle age. Nature 422:176–180
Eisen A (2009) Amyotrophic lateral sclerosis: a 40-year personal perspective. J Clin Neurosci 16:505–512
Ekestern E (2004) Neurotrophic factors and amyotrophic lateral sclerosis. Neurodegener Dis 1:88–100
Eliasson C, Sahlgren C, Berthold C, Stakeberg J, Celis J, Betsholtz C, Eriksson J, Pekny M (1999) Intermediate filament protein partnership in astrocytes. J Biol Chem 274:23996–24006
Fontana A, Fierz W, Wekerle H (1984) Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature 307:273–276
Foster CA, Howard LM, Schweitzer A, Persohn E, Hiestand PC, Balatoni B, Reuschel R, Beerli C, Schwartz M, Billich A (2007) Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J Pharmacol Exp Ther 323:469–475
Frohman EM, Vayuvegula B, Gupta S, van den Noort S (1988) Norepinephrine inhibits gamma-interferon-induced major histocompatibility class II (Ia) antigen expression on cultured astrocytes via beta-2-adrenergic signal transduction mechanisms. Proc Natl Acad Sci U S A 85:1292–1296
Gabrijel M, Kreft M, Zorec R (2008) Monitoring lysosomal fusion in electrofused hybridoma cells. Biochim Biophys Acta 1778:483–490
Garbuzova-Davis S, Saporta S, Haller E, Kolomey I, Bennett SP, Potter H, Sanberg PR (2007) Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS One 2:e1205
Gasparini S, Saviane C, Voronin LL, Cherubini E (2000) Silent synapses in the developing hippocampus: lack of functional AMPA receptors or low probability of glutamate release? Proc Natl Acad Sci U S A 97:9741–9746
Giaume C, Kirchhoff F, Matute C, Reichenbach A, Verkhratsky A (2007) Glia: the fulcrum of brain diseases. Cell Death Differ 14:1324–1335
Gordon G, Mulligan S, MacVicar B (2007) Astrocyte control of the cerebrovasculature. Glia 55:1214–1221
Grosche J, Matyash V, Möller T, Verkhratsky A, Reichenbach A, Kettenmann H (1999) Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat Neurosci 2:139–143
Grosche J, Kettenmann H, Reichenbach A (2002) Bergmann glial cells form distinct morphological structures to interact with cerebellar neurons. J Neurosci Res 68:138–149
Guček A, Vardjan N, Zorec R (2012) Exocytosis in astrocytes: transmitter release and membrane signal regulation. Neurochem Res 37:2351–2363
Gunnarson E, Zelenina M, Axehult G, Song Y, Bondar A, Krieger P, Brismar H, Zelenin S, Aperia A (2008) Identification of a molecular target for glutamate regulation of astrocyte water permeability. Glia 56:587–596
Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19:520–528
Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, Rao M, Eagle A, Kammesheidt A, Christensen A, Mendell JR, Burghes AH, Kaspar BK (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824–828
Hammerschmidt T, Kummer MP, Terwel D, Martinez A, Gorji A, Pape HC, Rommelfanger KS, Schroeder JP, Stoll M, Schultze J, Weinshenker D, Heneka MT (2013) Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice. Biol Psychiatry 73:454–463
Han W, Ng Y, Axelrod D, Levitan E (1999) Neuropeptide release by efficient recruitment of diffusing cytoplasmic secretory vesicles. Proc Natl Acad Sci U S A 96:14577–14582
Harris JJ, Jolivet R, Attwell D (2012) Synaptic energy use and supply. Neuron 75:762–777
Hasegawa H, Ma T, Skach W, Matthay MA, Verkman AS (1994) Molecular cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues. J Biol Chem 269:5497–5500
Hatton GI, Luckman SM, Bicknell RJ (1991) Adrenalin activation of beta 2-adrenoceptors stimulates morphological changes in astrocytes (pituicytes) cultured from adult rat neurohypophyses. Brain Res Bull 26:765–769
Haydon P (2001) GLIA: listening and talking to the synapse. Nat Rev Neurosci 2:185–193
Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009–1031
Hell SW, Wichmann J (1994) Breaking the diffraction resolution limit by stimulated emission: stimulated-emission-depletion fluorescence microscopy. Opt Lett 19:780–782
Hines DJ, Haydon PG (2013) Inhibition of a SNARE-sensitive pathway in astrocytes attenuates damage following stroke. J Neurosci 33:4234–4240
Hirt B, Gleiser C, Eckhard A, Mack AF, Müller M, Wolburg H, Löwenheim H (2011) All functional aquaporin-4 isoforms are expressed in the rat cochlea and contribute to the formation of orthogonal arrays of particles. Neuroscience 189:79–92
Huang YH, Bergles DE (2004) Glutamate transporters bring competition to the synapse. Curr Opin Neurobiol 14:346–352
Jahn R, Südhof T (1999) Membrane fusion and exocytosis. Annu Rev Biochem 68:863–911
Jaiswal JK, Andrews NW, Simon SM (2002) Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells. J Cell Biol 159:625–635
Jaiswal JK, Fix M, Takano T, Nedergaard M, Simon SM (2007) Resolving vesicle fusion from lysis to monitor calcium-triggered lysosomal exocytosis in astrocytes. Proc Natl Acad Sci U S A 104:14151–14156
Jean Y, Lercher L, Dreyfus C (2008) Glutamate elicits release of BDNF from basal forebrain astrocytes in a process dependent on metabotropic receptors and the PLC pathway. Neuron Glia Biol 4:35–42
Jeftinija SD, Jeftinija KV, Stefanovic G, Liu F (1996) Neuroligand-evoked calcium-dependent release of excitatory amino acids from cultured astrocytes. J Neurochem 66:676–684
Jorgacevski J, Potokar M, Grilc S, Kreft M, Liu W, Barclay JW, Bückers J, Medda R, Hell SW, Parpura V, Burgoyne RD, Zorec R (2011) Munc18–1 tuning of vesicle merger and fusion pore properties. J Neurosci 31:9055–9066
Jung JS, Bhat RV, Preston GM, Guggino WB, Baraban JM, Agre P (1994) Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci U S A 91:13052–13056
Junyent F, De Lemos L, Utrera J, Paco S, Aguado F, Camins A, Pallàs M, Romero R, Auladell C (2011) Content and traffic of taurine in hippocampal reactive astrocytes. Hippocampus 21:185–197
Ke C, Poon WS, Ng HK, Pang JC, Chan Y (2001) Heterogeneous responses of aquaporin-4 in oedema formation in a replicated severe traumatic brain injury model in rats. Neurosci Lett 301:21–24
Kirischuk S, Kettenmann H, Verkhratsky A (2007) Membrane currents and cytoplasmic sodium transients generated by glutamate transport in Bergmann glial cells. Pflugers Arch 454:245–252
Kofuji P, Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129:1045–1056
Kreft M, Zorec R (1997) Cell-attached measurements of attofarad capacitance steps in rat melanotrophs. Pflugers Arch 434:212–214
Kreft M, Stenovec M, Rupnik M, Grilc S, Krzan M, Potokar M, Pangrsic T, Haydon P, Zorec R (2004) Properties of Ca(2+)-dependent exocytosis in cultured astrocytes. Glia 46:437–445
Krzan M, Stenovec M, Kreft M, Pangrsic T, Grilc S, Haydon P, Zorec R (2003) Calcium-dependent exocytosis of atrial natriuretic peptide from astrocytes. J Neurosci 23:1580–1583
Li D, Ropert N, Koulakoff A, Giaume C, Oheim M (2008) Lysosomes are the major vesicular compartment undergoing Ca2+-regulated exocytosis from cortical astrocytes. J Neurosci 28:7648–7658
Li D, Hérault K, Silm K, Evrard A, Wojcik S, Oheim M, Herzog E, Ropert N (2013) Lack of evidence for vesicular glutamate transporter expression in mouse astrocytes. J Neurosci 33:4434–4455
Luckasson R, Reeve A (2001) Naming, defining, and classifying in mental retardation. Ment Retard 39:47–52
Malarkey EB, Parpura V (2011) Temporal characteristics of vesicular fusion in astrocytes: examination of synaptobrevin 2-laden vesicles at single vesicle resolution. J Physiol 589:4271–4300
Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163
Marcaggi P, Billups D, Attwell D (2003) The role of glial glutamate transporters in maintaining the independent operation of juvenile mouse cerebellar parallel fibre synapses. J Physiol 552:89–107
Martineau M, Galli T, Baux G, Mothet J (2008) Confocal imaging and tracking of the exocytotic routes for D-serine-mediated gliotransmission. Glia 56:1271–1284
Martineau M, Shi T, Puyal J, Knolhoff AM, Dulong J, Gasnier B, Klingauf J, Sweedler JV, Jahn R, Mothet JP (2013) Storage and uptake of D-serine into astrocytic synaptic-like vesicles specify gliotransmission. J Neurosci 33:3413–3423
McMahon T (1973) Size and shape in biology. Science 179:1201–1204
Milošević M, Stenovec M, Kreft M, Petrušić V, Stević Z, Trkov S, Andjus PR, Zorec R (2013) Immunoglobulins G from patients with sporadic amyotrophic lateral sclerosis affects cytosolic Ca2+ homeostasis in cultured rat astrocytes. Cell Calcium 54:17–25
Moe SE, Sorbo JG, Sogaard R, Zeuthen T, Petter Ottersen O, Holen T (2008) New isoforms of rat Aquaporin-4. Genomics 91:367–377
Montana V, Ni Y, Sunjara V, Hua X, Parpura V (2004) Vesicular glutamate transporter-dependent glutamate release from astrocytes. J Neurosci 24:2633–2642
Montana V, Malarkey E, Verderio C, Matteoli M, Parpura V (2006) Vesicular transmitter release from astrocytes. Glia 54:700–715
Murphy S, Pearce B, Jeremy J, Dandona P (1988) Astrocytes as eicosanoid-producing cells. Glia 1:241–245
Murthy VN, Schikorski T, Stevens CF, Zhu Y (2001) Inactivity produces increases in neurotransmitter release and synapse size. Neuron 32:673–682
Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615–622
Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY (2003) Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971:197–209
Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25:663–674
Nagelhus EA, Veruki ML, Torp R, Haug FM, Laake JH, Nielsen S, Agre P, Ottersen OP (1998) Aquaporin-4 water channel protein in the rat retina and optic nerve: polarized expression in Müller cells and fibrous astrocytes. J Neurosci 18:2506–2519
Nase G, Helm PJ, Enger R, Ottersen OP (2008) Water entry into astrocytes during brain edema formation. Glia 56:895–902
Nedergaard M, Dirnagl U (2005) Role of glial cells in cerebral ischemia. Glia 50:281–286
Nedergaard M, Ransom B, Goldman S (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530
Neely JD, Christensen BM, Nielsen S, Agre P (1999) Heterotetrameric composition of aquaporin-4 water channels. Biochemistry 38:11156–11163
Nicchia GP, Rossi A, Mola MG, Procino G, Frigeri A, Svelto M (2008) Actin cytoskeleton remodeling governs aquaporin-4 localization in astrocytes. Glia 56:1755–1766
Nicchia GP, Ficarella R, Rossi A, Giangreco I, Nicolotti O, Carotti A, Pisani F, Estivill X, Gasparini P, Svelto M, Frigeri A (2011) D184E mutation in aquaporin-4 gene impairs water permeability and links to deafness. Neuroscience 197:80–88
Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17:171–180
Nikolaev VO, Bünemann M, Hein L, Hannawacker A, Lohse MJ (2004) Novel single chain cAMP sensors for receptor-induced signal propagation. J Biol Chem 279:37215–37218
Nogami M, Shiga J, Takatsu A, Endo N, Ishiyama I (2001) Immunohistochemistry of atrial natriuretic peptide in brain infarction. Histochem J 33:87–90
O’Kane RL, Martínez-López I, DeJoseph MR, Viña JR, Hawkins RA (1999) Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. J Biol Chem 274:31891–31895
Olabarria M, Noristani HN, Verkhratsky A, Rodríguez JJ (2010) Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 58:831–838
Osborne KD, Lee W, Malarkey EB, Irving AJ, Parpura V (2009) Dynamic imaging of cannabinoid receptor 1 vesicular trafficking in cultured astrocytes. ASN Neuro 1. doi:10.1042/AN20090040
Pangrsic T, Potokar M, Haydon P, Zorec R, Kreft M (2006) Astrocyte swelling leads to membrane unfolding, not membrane insertion. J Neurochem 99:514–523
Pangrsic T, Potokar M, Stenovec M, Kreft M, Fabbretti E, Nistri A, Pryazhnikov E, Khiroug L, Giniatullin R, Zorec R (2007) Exocytotic release of ATP from cultured astrocytes. J Biol Chem 282:28749–28758
Papadopoulos MC, Manley GT, Krishna S, Verkman AS (2004) Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J 18:1291–1293
Parpura V, Zorec R (2010) Gliotransmission: exocytotic release from astrocytes. Brain Res Rev 63:83–92
Parpura V, Basarsky T, Liu F, Jeftinija K, Jeftinija S, Haydon P (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747
Parpura V, Liu F, Brethorst S, Jeftinija K, Jeftinija S, Haydon PG (1995) Alpha-latrotoxin stimulates glutamate release from cortical astrocytes in cell culture. FEBS Lett 360:266–270
Parpura V, Baker B, Jeras M, Zorec R (2010) Regulated exocytosis in astrocytic signal integration. Neurochem Int 57:451–459
Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A (2012) Glial cells in (patho)physiology. J Neurochem 121:4–27
Pasantes-Morales H, Franco R, Ochoa L, Ordaz B (2002) Osmosensitive release of neurotransmitter amino acids: relevance and mechanisms. Neurochem Res 27:59–65
Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG (2005) Astrocytic purinergic signaling coordinates synaptic networks. Science 310:113–116
Pehar M, Cassina P, Vargas MR, Castellanos R, Viera L, Beckman JS, Estévez AG, Barbeito L (2004) Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J Neurochem 89:464–473
Pekny M, Eliasson C, Chien C, Kindblom L, Liem R, Hamberger A, Betsholtz C (1998) GFAP-deficient astrocytes are capable of stellation in vitro when cocultured with neurons and exhibit a reduced amount of intermediate filaments and an increased cell saturation density. Exp Cell Res 239:332–343
Pelkmans L, Zerial M (2005) Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436:128–133
Potokar M, Kreft M, Pangrsic T, Zorec R (2005) Vesicle mobility studied in cultured astrocytes. Biochem Biophys Res Commun 329:678–683
Potokar M, Kreft M, Li L, Daniel Andersson J, Pangrsic T, Chowdhury H, Pekny M, Zorec R (2007) Cytoskeleton and vesicle mobility in astrocytes. Traffic 8:12–20
Potokar M, Stenovec M, Kreft M, Kreft ME, Zorec R (2008) Stimulation inhibits the mobility of recycling peptidergic vesicles in astrocytes. Glia 56:135–144
Potokar M, Kreft M, Lee S, Takano H, Haydon P, Zorec R (2009) Trafficking of astrocytic vesicles in hippocampal slices. Biochem Biophys Res Commun 390:1192–1196
Potokar M, Stenovec M, Gabrijel M, Li L, Kreft M, Grilc S, Pekny M, Zorec R (2010) Intermediate filaments attenuate stimulation-dependent mobility of endosomes/lysosomes in astrocytes. Glia 58:1208–1219
Potokar M, Stenovec M, Kreft M, Gabrijel M, Zorec R (2011) Physiopathologic dynamics of vesicle traffic in astrocytes. Histol Histopathol 26:277–284
Potokar M, Lacovich V, Chowdhury HH, Kreft M, Zorec R (2012) Rab4 and Rab5 GTPase are required for directional mobility of endocytic vesicles in astrocytes. Glia 60:594–604
Potokar M, Stenovec M, Jorgačevski J, Holen T, Kreft M, Ottersen OP, Zorec R (2013a) Regulation of AQP4 surface expression via vesicle mobility in astrocytes. Glia 61:917–928
Potokar M, Vardjan N, Stenovec M, Gabrijel M, Trkov S, Jorgačevski J, Kreft M, Zorec R (2013b) Astrocytic vesicle mobility in health and disease. Int J Mol Sci 14:11238–11258
Prebil M, Chowdhury HH, Zorec R, Kreft M (2011a) Changes in cytosolic glucose level in ATP stimulated live astrocyte cells. Biochem Biophys Res Commun 405:308–313
Prebil M, Vardjan N, Jensen J, Zorec R, Kreft M (2011b) Dynamic monitoring of cytosolic glucose in single astrocytes. Glia 59:903–913
Risher WC, Andrew RD, Kirov SA (2009) Real-time passive volume responses of astrocytes to acute osmotic and ischemic stress in cortical slices and in vivo revealed by two-photon microscopy. Glia 57:207–221
Robinson MB (2002) Regulated trafficking of neurotransmitter transporters: common notes but different melodies. J Neurochem 80:1–11
Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38:73–84
Seifert G, Schilling K, Steinhäuser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206
Shain W, Forman DS, Madelian V, Turner JN (1987) Morphology of astroglial cells is controlled by beta-adrenergic receptors. J Cell Biol 105:2307–2314
Shinohara Y, Hosoya A, Hirase H (2013) Experience enhances gamma oscillations and interhemispheric asymmetry in the hippocampus. Nat Commun 4:1652
Shrikant P, Benveniste EN (1996) The central nervous system as an immunocompetent organ: role of glial cells in antigen presentation. J Immunol 157:1819–1822
Soos JM, Morrow J, Ashley TA, Szente BE, Bikoff EK, Zamvil SS (1998) Astrocytes express elements of the class II endocytic pathway and process central nervous system autoantigen for presentation to encephalitogenic T cells. J Immunol 161:5959–5966
Stehberg J, Moraga-Amaro R, Salazar C, Becerra A, Echeverría C, Orellana JA, Bultynck G, Ponsaerts R, Leybaert L, Simon F, Sáez JC, Retamal MA (2012) Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala. FASEB J 26:3649–3657
Stenovec M, Kreft M, Grilc S, Potokar M, Kreft M, Pangrsic T, Zorec R (2007) Ca2+-dependent mobility of vesicles capturing anti-VGLUT1 antibodies. Exp Cell Res 313:3809–3818
Stenovec M, Kreft M, Grilc S, Pangrsic T, Zorec R (2008) EAAT2 density at the astrocyte plasma membrane and Ca(2+)-regulated exocytosis. Mol Membr Biol 25:203–215
Stenovec M, Milošević M, Petrušić V, Potokar M, Stević Z, Prebil M, Kreft M, Trkov S, Andjus PR, Zorec R (2011) Amyotrophic lateral sclerosis immunoglobulins G enhance the mobility of Lysotracker-labelled vesicles in cultured rat astrocytes. Acta Physiol (Oxf) 203:457–471
Stevens B (2008) Neuron-astrocyte signaling in the development and plasticity of neural circuits. Neurosignals 16:278–288
Stout CE, Costantin JL, Naus CC, Charles AC (2002) Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem 277:10482–10488
Sutin J, Shao Y (1992) Resting and reactive astrocytes express adrenergic receptors in the adult rat brain. Brain Res Bull 29:277–284
Takano T, Kang J, Jaiswal JK, Simon SM, Lin JH, Yu Y, Li Y, Yang J, Dienel G, Zielke HR, Nedergaard M (2005) Receptor-mediated glutamate release from volume sensitive channels in astrocytes. Proc Natl Acad Sci U S A 102:16466–16471
Taraska J, Perrais D, Ohara-Imaizumi M, Nagamatsu S, Almers W (2003) Secretory granules are recaptured largely intact after stimulated exocytosis in cultured endocrine cells. Proc Natl Acad Sci U S A 100:2070–2075
Theodosis DT, Poulain DA, Oliet SH (2008) Activity-dependent structural and functional plasticity of astrocyte-neuron interactions. Physiol Rev 88:983–1008
Thrane AS, Rappold PM, Fujita T, Torres A, Bekar LK, Takano T, Peng W, Wang F, Thrane VR, Enger R, Haj-Yasein NN, Skare Ø, Holen T, Klungland A, Ottersen OP, Nedergaard M, Nagelhus EA (2011) Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema. Proc Natl Acad Sci U S A 108:846–851
Trkov S, Stenovec M, Kreft M, Potokar M, Parpura V, Davletov B, Zorec R (2012) Fingolimod–a sphingosine-like molecule inhibits vesicle mobility and secretion in astrocytes. Glia 60:1406–1416
Turner G (1996) Finding genes on the X chromosome by which homo may have become sapiens. Am J Hum Genet 58:1109–1110
Tvaruskó W, Bentele M, Misteli T, Rudolf R, Kaether C, Spector D, Gerdes H, Eils R (1999) Time-resolved analysis and visualization of dynamic processes in living cells. Proc Natl Acad Sci U S A 96:7950–7955
Urushitani M, Sik A, Sakurai T, Nukina N, Takahashi R, Julien JP (2006) Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci 9:108–118
Valtorta F, Meldolesi J, Fesce R (2001) Synaptic vesicles: is kissing a matter of competence? Trends Cell Biol 11:324–328
Van Damme P, Dewil M, Robberecht W, Van Den Bosch L (2005) Excitotoxicity and amyotrophic lateral sclerosis. Neurodegener Dis 2:147–159
Vardjan N, Gabrijel M, Potokar M, Svajger U, Kreft M, Jeras M, de Pablo Y, Faiz M, Pekny M, Zorec R (2012) IFN-γ-induced increase in the mobility of MHC class II compartments in astrocytes depends on intermediate filaments. J Neuroinflamm 9:144
Vascotto F, Lankar D, Faure-André G, Vargas P, Diaz J, Le Roux D, Yuseff MI, Sibarita JB, Boes M, Raposo G, Mougneau E, Glaichenhaus N, Bonnerot C, Manoury B, Lennon-Duménil AM (2007) The actin-based motor protein myosin II regulates MHC class II trafficking and BCR-driven antigen presentation. J Cell Biol 176:1007–1019
Verderio C, Cagnoli C, Bergami M, Francolini M, Schenk U, Colombo A, Riganti L, Frassoni C, Zuccaro E, Danglot L, Wilhelm C, Galli T, Canossa M, Matteoli M (2012) TI-VAMP/VAMP7 is the SNARE of secretory lysosomes contributing to ATP secretion from astrocytes. Biol Cell 104:213–228
Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7:399–412
Vesce S, Bezzi P, Volterra A (1999) The active role of astrocytes in synaptic transmission. Cell Mol Life Sci 56:991–1000
Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640
Vyas JM, Kim YM, Artavanis-Tsakonas K, Love JC, Van der Veen AG, Ploegh HL (2007) Tubulation of class II MHC compartments is microtubule dependent and involves multiple endolysosomal membrane proteins in primary dendritic cells. J Immunol 178:7199–7210
Wacker I, Kaether C, Krömer A, Migala A, Almers W, Gerdes H (1997) Microtubule-dependent transport of secretory vesicles visualized in real time with a GFP-tagged secretory protein. J Cell Sci 110(Pt 13):1453–1463
Wang Z, Haydon PG, Yeung ES (2000) Direct observation of calcium-independent intercellular ATP signaling in astrocytes. Anal Chem 72:2001–2007
Wilhelmsson U, Li L, Pekna M, Berthold C, Blom S, Eliasson C, Renner O, Bushong E, Ellisman M, Morgan T, Pekny M (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 24:5016–5021
Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M, Ellisman MH, Pekny M (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci U S A 103:17513–17518
Wubbolts R, Fernandez-Borja M, Jordens I, Reits E, Dusseljee S, Echeverri C, Vallee RB, Neefjes J (1999) Opposing motor activities of dynein and kinesin determine retention and transport of MHC class II-containing compartments. J Cell Sci 112(Pt 6):785–795
Yamamoto N, Yoneda K, Asai K, Sobue K, Tada T, Fujita Y, Katsuya H, Fujita M, Aihara N, Mase M, Yamada K, Miura Y, Kato T (2001) Alterations in the expression of the AQP family in cultured rat astrocytes during hypoxia and reoxygenation. Brain Res Mol Brain Res 90:26–38
Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864
Zeinstra E, Wilczak N, De Keyser J (2000) [3H]dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain. Neurosci Lett 289:75–77
Zhang JM, Wang HK, Ye CQ, Ge W, Chen Y, Jiang ZL, Wu CP, Poo MM, Duan S (2003) ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 40:971–982
Zhang Q, Fukuda M, Van Bockstaele E, Pascual O, Haydon P (2004a) Synaptotagmin IV regulates glial glutamate release. Proc Natl Acad Sci U S A 101:9441–9446
Zhang Q, Pangrsic T, Kreft M, Krzan M, Li N, Sul J, Halassa M, Van Bockstaele E, Zorec R, Haydon P (2004b) Fusion-related release of glutamate from astrocytes. J Biol Chem 279:12724–12733
Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Hadlock K, Jin X, Reis J, Narvaez A, McGrath MS (2005) Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 159:215–224
Zhang Z, Chen G, Zhou W, Song A, Xu T, Luo Q, Wang W, Gu XS, Duan S (2007) Regulated ATP release from astrocytes through lysosome exocytosis. Nat Cell Biol 9:945–953
Zimmermann H (1994) Signalling via ATP in the nervous system. Trends Neurosci 17:420–426
Zonta M, Angulo M, Gobbo S, Rosengarten B, Hossmann K, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43–50
Zorec R, Araque A, Carmignoto G, Haydon PG, Verkhratsky A, Parpura V (2012) Astroglial excitability and gliotransmission: an appraisal of Ca2+ as a signalling route. ASN Neuro 4. doi:10.1042/AN20110061
Acknowledgments
The authors’ work is supported by grants from the Slovenian Research Agency (P3 310, J3 4051, J3 4146, L3 3654; J3 3236), CIPKEBIP, and COST Nanonet.
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Vardjan, N. et al. (2014). Pathophysiology of Vesicle Dynamics in Astrocytes. In: Parpura, V., Verkhratsky, A. (eds) Pathological Potential of Neuroglia. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0974-2_3
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