What Is the Role of Astrocyte Calcium in Neurophysiology?
2008; Cell Press; Volume: 59; Issue: 6 Linguagem: Inglês
10.1016/j.neuron.2008.09.004
ISSN1097-4199
AutoresCendra Agulhon, Jeremy Petravicz, Allison B. McMullen, Elizabeth J. Sweger, Suzanne K. Minton, Sarah Taves, Kristen B. Casper, Todd A. Fiacco, Ken D. McCarthy,
Tópico(s)Epilepsy research and treatment
ResumoAstrocytes comprise approximately half of the volume of the adult mammalian brain and are the primary neuronal structural and trophic supportive elements. Astrocytes are organized into distinct nonoverlapping domains and extend elaborate and dense fine processes that interact intimately with synapses and cerebrovasculature. The recognition in the mid 1990s that astrocytes undergo elevations in intracellular calcium concentration following activation of G protein-coupled receptors by synaptically released neurotransmitters demonstrated not only that astrocytes display a form of excitability but also that astrocytes may be active participants in brain information processing. The roles that astrocytic calcium elevations play in neurophysiology and especially in modulation of neuronal activity have been intensely researched in recent years. This review will summarize the current understanding of the function of astrocytic calcium signaling in neurophysiological processes and discuss areas where the role of astrocytes remains controversial and will therefore benefit from further study. Astrocytes comprise approximately half of the volume of the adult mammalian brain and are the primary neuronal structural and trophic supportive elements. Astrocytes are organized into distinct nonoverlapping domains and extend elaborate and dense fine processes that interact intimately with synapses and cerebrovasculature. The recognition in the mid 1990s that astrocytes undergo elevations in intracellular calcium concentration following activation of G protein-coupled receptors by synaptically released neurotransmitters demonstrated not only that astrocytes display a form of excitability but also that astrocytes may be active participants in brain information processing. The roles that astrocytic calcium elevations play in neurophysiology and especially in modulation of neuronal activity have been intensely researched in recent years. This review will summarize the current understanding of the function of astrocytic calcium signaling in neurophysiological processes and discuss areas where the role of astrocytes remains controversial and will therefore benefit from further study. When neuroglia were first described, there was considerable debate as to whether neuroglia were a connective tissue or a true population of cells (Somjen, 1988Somjen G.G. Nervenkitt: notes on the history of the concept of neuroglia.Glia. 1988; 1: 2-9Crossref PubMed Google Scholar). While this issue was resolved in the late 1800s, little attention was paid to the role of glia in neurophysiology for nearly a century. During this period, neuroscientists generally considered glia as chemical and physical insulators that enabled neurons to carry out the diverse functions of the brain. This view was reinforced by the findings of early neurophysiologists who impaled glial cells with sharp electrodes and found only passive membrane currents. Given the large fraction of brain contributed by glia, the prevailing view until the early 1970s was that over half of the mammalian brain was, in effect, silent. This view began to change as investigators found that glial cells in culture exhibited a large number of G protein-coupled receptors (GPCRs) linked to a diverse array of intracellular signaling cascades (McCarthy and de Vellis, 1978McCarthy K.D. de Vellis J. Alpha-adrenergic receptor modulation of beta-adrenergic, adenosine and prostaglandin E1 increased adenosine 3′:5′- cyclic monophosphate levels in primary cultures of glia.J. Cyclic Nucleotide Res. 1978; 4: 15-26PubMed Google Scholar, van Calker and Hamprecht, 1981van Calker D. Hamprecht B. Effects of neurohormones on glial cells.in: Federoff S. Hertz L. Advances in Cellular Neuribiology. Academic Press, Orlando, FL1981: 32-55Google Scholar, van Calker et al., 1978van Calker D. Muller M. Hamprecht B. Adrenergic alpha and beta-receptors expressed by the same cell type in primary culture of perinatal mouse brain.J. Neurochem. 1978; 30: 713-718Crossref PubMed Google Scholar). Concerns about the expression of GPCRs by glia being a "culture" phenomenon were put to rest as it was demonstrated that glia in situ and in vivo also express GPCRs (Porter and McCarthy, 1997Porter J.T. McCarthy K.D. Astrocytic neurotransmitter receptors in situ and in vivo.Prog. Neurobiol. 1997; 51: 439-455Crossref PubMed Scopus (282) Google Scholar). Today, it is generally accepted that glia throughout the brain and spinal cord as well as peripheral glia residing within ganglia and aligning axons express members of most of the different families of GPCRs known to be expressed by neurons (Porter and McCarthy, 1997Porter J.T. McCarthy K.D. Astrocytic neurotransmitter receptors in situ and in vivo.Prog. Neurobiol. 1997; 51: 439-455Crossref PubMed Scopus (282) Google Scholar). Stimulation of these GPCRs evokes a variety of glial cell responses, the most studied of which is elevation of intracellular calcium (Ca2+) concentration that is widely considered a form of glial excitability. The question is no longer whether glia exhibit GPCRs, but under what conditions are these GPCRs activated and what is the role of glial GPCR-mediated signaling in neurophysiology? Like the term "neuron," glia refers to a diverse set of cell types that are likely to carry out distinct functions in neurophysiology. There are four major groups of glial cells in the nervous system: (1) Schwann cells and oligodendrocytes, which produce and wrap layers of myelin around axons in the peripheral and central nervous systems, respectively; (2) microglia, the immune cell type of the nervous system, which participate in inflammatory responses; (3) nerve/glial antigen 2 (NG2)-positive glia, which include oligodendrocyte and astrocyte progenitor cells as well as NG2+ cells that persist in the mature brain; and (4) astrocytes. Astrocytes are found throughout the brain and spinal cord and, on the basis of number, surface area, and volume, are the predominant glial cell type. There are many distinct subsets of astrocytes that can be distinguished on the basis of their morphology and biochemical characteristics. For example, Mueller glia in the retina and Bergmann glia in the cerebellum are generally grouped with astrocytes because of their expression of glial fibrillary acidic protein (GFAP) but exhibit striking differences in morphology, pharmacology, and physiology (Grosche et al., 1999Grosche J. Matyash V. Moller T. Verkhratsky A. Reichenbach A. Kettenmann H. Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells.Nat. Neurosci. 1999; 2: 139-143Crossref PubMed Scopus (357) Google Scholar, Grosche et al., 2002Grosche J. Kettenmann H. Reichenbach A. Bergmann glial cells form distinct morphological structures to interact with cerebellar neurons.J. Neurosci. Res. 2002; 68: 138-149Crossref PubMed Scopus (85) Google Scholar, Metea and Newman, 2006Metea M.R. Newman E.A. Calcium signaling in specialized glial cells.Glia. 2006; 54: 650-655Crossref PubMed Scopus (39) Google Scholar, Pinto and Gotz, 2007Pinto L. Gotz M. Radial glial cell heterogeneity–the source of diverse progeny in the CNS.Prog. Neurobiol. 2007; 83: 2-23Crossref PubMed Scopus (107) Google Scholar). It is likely that, even within a localized brain region, adjacent astrocytes that appear identical morphologically and immunocytochemically may vary in their expression of GPCRs and their response to activation of GPCRs. While such diversity is generally accepted when considering neurons, it is rarely taken into account when interpreting data derived from astrocytes. Protoplasmic astrocytes are the most common type of astrocytes. These cells exhibit a very complex morphology and contact most, if not all, other cell types in the brain and spinal cord. The morphology of an astrocyte resembles a bush with processes radiating out from a central cell body (Figure 1A). Within the CA1 stratum radiatum of the hippocampus, an individual astrocyte has a soma diameter of 7–9 μm and, with its fine processes, occupies a volume of ∼66,000 μm3 (Bushong et al., 2002Bushong E.A. Martone M.E. Jones Y.Z. Ellisman M.H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains.J. Neurosci. 2002; 22: 183-192Crossref PubMed Google Scholar). Interestingly, individual astrocytes tend to occupy distinct, nonoverlapping domains (Figure 1A) (Bushong et al., 2002Bushong E.A. Martone M.E. Jones Y.Z. Ellisman M.H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains.J. Neurosci. 2002; 22: 183-192Crossref PubMed Google Scholar). The fine processes of an individual astrocyte are connected to one another through reflexive gap junctions and to other astrocytes via gap junctions at their boundaries. Patch-clamping a single astrocyte with an electrode filled with a gap-junction-permeable dye rapidly leads to the filling of hundreds, if not thousands, of astrocytes (Konietzko and Muller, 1994Konietzko U. Muller C.M. Astrocytic dye coupling in rat hippocampus: topography, developmental onset, and modulation by protein kinase C.Hippocampus. 1994; 4: 297-306Crossref PubMed Scopus (50) Google Scholar). Astrocytes likely function as a syncytium contacting essentially all other cellular elements in brain, including neurons, oligodendrocytes, NG2+ cells, microglia, and vasculature. A striking feature of astrocytes is that processes from a single astrocyte can envelop approximately 140,000 synapses (Figure 1B) (Bushong et al., 2002Bushong E.A. Martone M.E. Jones Y.Z. Ellisman M.H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains.J. Neurosci. 2002; 22: 183-192Crossref PubMed Google Scholar), while >99% of the cerebrovascular surface is ensheathed by astrocyte processes (Kacem et al., 1998Kacem K. Lacombe P. Seylaz J. Bonvento G. Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study.Glia. 1998; 23: 1-10Crossref PubMed Scopus (136) Google Scholar, Rama Rao et al., 2003Rama Rao K.V. Chen M. Simard J.M. Norenberg M.D. Increased aquaporin-4 expression in ammonia-treated cultured astrocytes.Neuroreport. 2003; 14: 2379-2382Crossref PubMed Google Scholar, Simard et al., 2003Simard M. Arcuino G. Takano T. Liu Q.S. Nedergaard M. Signaling at the gliovascular interface.J. Neurosci. 2003; 23: 9254-9262PubMed Google Scholar, Haydon and Carmignoto, 2006Haydon P.G. Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling.Physiol. 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Understanding how the different microdomains of astrocytes interact with neighboring cellular elements will be critical to determining their role in neurophysiology and neuropathology. The morphology of astrocytes places them in a unique situation to be able to listen to and respond to most cellular elements. Astrocytes exhibit a large number of GPCRs linked to Ca2+ mobilization from internal stores, most of them being Gq-coupled GPCRs (Gq GPCRs). While these receptors can be experimentally activated in situ by exogenous application of agonists (Porter and McCarthy, 1995aPorter J.T. McCarthy K.D. Adenosine receptors modulate [Ca2+]i in hippocampal astrocytes in situ.J. Neurochem. 1995; 65: 1515-1523Crossref PubMed Google Scholar, Porter and McCarthy, 1995bPorter J.T. McCarthy K.D. GFAP-positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca2+]i.Glia. 1995; 13: 101-112Crossref PubMed Google Scholar), they are also activated by neurotransmitters released from presynaptic terminals (Araque et al., 2002Araque A. Martin E.D. Perea G. Arellano J.I. Buno W. Synaptically released acetylcholine evokes Ca2+ elevations in astrocytes in hippocampal slices.J. Neurosci. 2002; 22: 2443-2450Crossref PubMed Google Scholar, Kang et al., 1998Kang J. Jiang L. Goldman S.A. Nedergaard M. Astrocyte-mediated potentiation of inhibitory synaptic transmission.Nat. Neurosci. 1998; 1: 683-692Crossref PubMed Google Scholar, Navarrete and Araque, 2008Navarrete M. Araque A. Endocannabinoids mediate neuron-astrocyte communication.Neuron. 2008; 57: 883-893Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, Pasti et al., 1997Pasti L. Volterra A. Pozzan T. Carmignoto G. 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Evidence for a reciprocal effect of astrocytes on synaptic transmission through the Gq GPCR-mediated Ca2+-dependent release of neuroactive molecules (called gliotransmitters) was reported in vitro and in situ when Gq GPCR agonist application elicited Ca2+ increases in astrocytes, which correlated to changes in neuronal ionotropic glutamate receptor (iGluR) activity (Parpura et al., 1994Parpura V. Basarsky T.A. Liu F. Jeftinija K. Jeftinija S. Haydon P.G. Glutamate-mediated astrocyte-neuron signalling. 1994; 369: 744-774Google Scholar, Pasti et al., 1997Pasti L. Volterra A. Pozzan T. Carmignoto G. Intracellular calcium oscillations in astrocytes: A highly plastic, bidirectional form of communication between neurons and astrocytes in situ.J. Neurosci. 1997; 17: 7817-7830Crossref PubMed Google Scholar). Since these reports, several laboratories have reported that Ca2+ elevations in a small fraction of astrocytes and under certain conditions in situ can result in the release of gliotransmitters, including glutamate, ATP, and D-serine, that bind to pre- and/or postsynaptic neuronal receptors to modulate synaptic transmission and activity (Bezzi et al., 1998Bezzi P. Carmignoto G. Pasti L. Vesce S. Rossi D. Rizzini B.L. Pozzan T. Volterra A. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes.Nature. 1998; 391: 281-285Crossref PubMed Scopus (734) Google Scholar, Fiacco and McCarthy, 2004Fiacco T.A. McCarthy K.D. Intracellular astrocyte calcium waves in situ increase the frequency of spontaneous AMPA receptor currents in CA1 pyramidal neurons.J. Neurosci. 2004; 24: 722-732Crossref PubMed Scopus (178) Google Scholar, Kang et al., 1998Kang J. Jiang L. Goldman S.A. Nedergaard M. Astrocyte-mediated potentiation of inhibitory synaptic transmission.Nat. 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The recognition of the bidirectional communication between neurons and astrocytes at the synapse led to the concept of the "tripartite synapse" (Figure 2), in which the astrocyte, in addition to pre- and postsynaptic compartments, is a functional component of the synapse. A primary focus of this review is to discuss recent findings that have shaped our current understanding of the role of astrocyte Gq GPCR-mediated Ca2+ elevations on neuronal-astrocyte communication, focusing on the concept of "gliotransmission" and discussing both the issues that are well accepted and the ones that are currently in dispute. The most widely accepted mechanism for astrocytic Ca2+ increases is the canonical phospholipase C (PLC)/inositol 1,4,5-trisphosphate (IP3) pathway. Upon Gq GPCR activation, PLC hydrolyzes the membrane lipid phosphatidylinositol 4,5-bisphosphate to generate diacylglycerol (DAG) and IP3, leading to IP3 receptor (IP3R) activation and Ca2+ release from the endoplasmic reticulum (ER). This is based on an exhaustive amount of data from both cultured astroglia and in situ astrocytes and has been the subject of numerous reviews (Fiacco and McCarthy, 2006Fiacco T.A. McCarthy K.D. Astrocyte calcium elevations: properties, propagation, and effects on brain signaling.Glia. 2006; 54: 676-690Crossref PubMed Scopus (106) Google Scholar, Parri and Crunelli, 2003Parri H.R. Crunelli V. The role of Ca2+ in the generation of spontaneous astrocytic Ca2+ oscillations.Neuroscience. 2003; 120: 979-992Crossref PubMed Scopus (70) Google Scholar, Scemes, 2000Scemes E. Components of astrocytic intercellular calcium signaling.Mol. Neurobiol. 2000; 22: 167-179Crossref PubMed Scopus (53) Google Scholar, Scemes and Giaume, 2006Scemes E. Giaume C. Astrocyte calcium waves: what they are and what they do.Glia. 2006; 54: 716-725Crossref PubMed Scopus (188) Google Scholar, Volterra and Steinhauser, 2004Volterra A. Steinhauser C. Glial modulation of synaptic transmission in the hippocampus.Glia. 2004; 47: 249-257Crossref PubMed Scopus (83) Google Scholar). Using a knockout (KO) of the IP3R type 2 (IP3R2), it has been recently demonstrated that, within the hippocampus, IP3R2 is the primary functional IP3R subtype in astrocytes in situ (Petravicz et al., 2008Petravicz J. Fiacco T.A. McCarthy K.D. Loss of IP3 receptor-dependent Ca2+ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity.J. Neurosci. 2008; 28: 4967-4973Crossref PubMed Scopus (91) Google Scholar). These data are consistent with data in cultured astroglia showing that Ca2+ release sites correlate with IP3R2 immunostaining and that IP3R2 associates with other members of the PLC/IP3 pathway in lipid rafts (Sheppard et al., 1997Sheppard C.A. Simpson P.B. Sharp A.H. Nucifora F.C. Ross C.A. Lange G.D. Russell J.T. Comparison of type 2 inositol 1,4,5-trisphosphate receptor distribution and subcellular Ca2+ release sites that support Ca2+ waves in cultured astrocytes.J. Neurochem. 1997; 68: 2317-2327Crossref PubMed Google Scholar, Weerth et al., 2007Weerth S.H. Holtzclaw L.A. Russell J.T. Signaling proteins in raft-like microdomains are essential for Ca2+ wave propagation in glial cells.Cell Calcium. 2007; 41: 155-167Crossref PubMed Scopus (44) Google Scholar). In addition, immunostaining for IP3Rs in rodent brain sections indicates that astrocytes express primarily IP3R2, while type 1 and 3 IP3Rs are preferentially found in neurons (Hertle and Yeckel, 2007Hertle D.N. Yeckel M.F. Distribution of inositol-1,4,5-trisphosphate receptor isotypes and ryanodine receptor isotypes during maturation of the rat hippocampus.Neuroscience. 2007; 150: 625-638Crossref PubMed Scopus (38) Google Scholar, Holtzclaw et al., 2002Holtzclaw L.A. Pandhit S. Bare D.J. Mignery G.A. Russell J.T. Astrocytes in adult rat brain express type 2 inositol 1,4,5-trisphosphate receptors.Glia. 2002; 39: 69-84Crossref PubMed Scopus (47) Google Scholar, Sharp et al., 1999Sharp A.H. Nucifora Jr., F.C. Blondel O. Sheppard C.A. Zhang C. Snyder S.H. Russell J.T. Ryugo D.K. Ross C.A. Differential cellular expression of isoforms of inositol 1,4,5-triphosphate receptors in neurons and glia in brain.J. Comp. Neurol. 1999; 406: 207-220Crossref PubMed Scopus (92) Google Scholar). While the mechanisms of astrocytic Ca2+ increases in response to Gq GPCR activation are relatively well understood, less is known about (1) how astrocytic second messenger pathways may be regulating the spatiotemporal dynamics of Gq GPCR-mediated Ca2+ transients and (2) how the interactions among the Gq GPCR signaling molecules contribute to a cellular response. Several factors can influence the activity of IP3Rs, including the cytoplasmic Ca2+ elevations themselves that activate IP3Rs due to the coagonistic action of Ca2+ on these receptors, the additional generation of IP3 through the Ca2+-dependent activation of PLC, and the phosphorylation and consequent potentiation of IP3Rs following ATP binding to the receptor (Foskett et al., 2007Foskett J.K. White C. Cheung K.H. Mak D.O. Inositol trisphosphate receptor Ca2+ release channels.Physiol. Rev. 2007; 87: 593-658Crossref PubMed Scopus (395) Google Scholar). Furthermore, studies of the DAG/protein kinase C (PKC) pathway indicate that PKC is involved in the termination of astrocytic Ca2+ transients (Codazzi et al., 2001Codazzi F. Teruel M.N. Meyer T. Control of astrocyte Ca(2+) oscillations and waves by oscillating translocation and activation of protein kinase C.Curr. Biol. 2001; 11: 1089-1097Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, Parri and Crunelli, 2003Parri H.R. Crunelli V. The role of Ca2+ in the generation of spontaneous astrocytic Ca2+ oscillations.Neuroscience. 2003; 120: 979-992Crossref PubMed Scopus (70) Google Scholar). While the molecular target of PKC phosphorylation remains unknown, the two most likely candidates are either Gq GPCRs or the IP3R itself. Further research into second messenger regulation will provide a better understanding of the signaling mechanisms governing astrocyte PLC-dependent Ca2+ regulation. Astrocytic Ca2+ elevations following stimulation of neuronal afferents are attributed to activation of astrocytic Gq GPCRs and not to activation of voltage-gated Ca2+ channels (VGCCs) (Beck et al., 2004Beck A. Nieden R.Z. Schneider H.P. Deitmer J.W. Calcium release from intracellular stores in rodent astrocytes and neurons in situ.Cell Calcium. 2004; 35: 47-58Crossref PubMed Scopus (55) Google Scholar, Carmignoto et al., 1998Carmignoto G. Pasti L. Pozzan T. On the role of voltage-dependent calcium channels in calcium signaling of astrocytes in situ.J. Neurosci. 1998; 18: 4637-4645PubMed Google Scholar, Duffy and MacVicar, 1994Duffy S. MacVicar B.A. Potassium-dependent calcium influx in acutely isolated hippocampal astrocytes.Neuroscience. 1994; 61: 51-61Crossref PubMed Scopus (61) Google Scholar, Jabs et al., 1994Jabs R. Kirchhoff F. Kettenmann H. Steinhauser C. Kainate activates Ca(2+)-permeable glutamate receptors and blocks voltage-gated K+ currents in glial cells of mouse hippocampal slices.Pflugers Arch. 1994; 426: 310-319Crossref PubMed Scopus (68) Google Scholar, Nett et al., 2002Nett W.J. Oloff S.H. McCarthy K.D. Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity.J. Neurophysiol. 2002; 87: 528-537PubMed Google Scholar, Parri and Crunelli, 2003Parri H.R. Crunelli V. The role of Ca2+ in the generation of spontaneous astrocytic Ca2+ oscillations.Neuroscience. 2003; 120: 979-992Crossref PubMed Scopus (70) Google Scholar, Porter and McCarthy, 1995bPorter J.T. McCarthy K.D. GFAP-positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca2+]i.Glia. 1995; 13: 101-112Crossref PubMed Google Scholar, Straub et al., 2006Straub S.V. Bonev A.D. Wilkerson M.K. Nelson M.T. Dynamic inositol trisphosphate-mediated calcium signals within astrocytic endfeet underlie vasodilation of cerebral arterioles.J. Gen. Physiol. 2006; 128: 659-669Crossref PubMed Scopus (35) Google Scholar). However, while astrocytic VGCCs do not seem to play a role in the initiation of evoked astrocytic Ca2+ increases, they may be important for initiating Ca2+ oscillations that occur independent of neuronal input, generally referred to as spontaneous or intrinsic astrocytic Ca2+ oscillations (Aguado et al., 2002Aguado F. Espinosa-Parrilla J.F. Carmona M.A. Soriano E. Neuronal activity regulates correlated network properties of spontaneous calcium transients in astrocytes in situ.J. Neurosci. 2002; 22: 9430-9444Crossref PubMed Google Scholar, Parri et al., 2001Parri H.R. Gould T.M. Crunelli V. Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation.Nat. Neurosci. 2001; 4: 803-812Crossref PubMed Scopus (315) Google Scholar, Parri and Crunelli, 2003Parri H.R. Crunelli V. The role of Ca2+ in the generation of spontaneous astrocytic Ca2+ oscillations.Neuroscience. 2003; 120: 979-992Crossref PubMed Scopus (70) Google Scholar). To date, there is little convincing evidence that astrocytes in situ exhibit ryanodine receptor-mediated increases in Ca2+ (Beck et al., 2004Beck A. Nieden R.Z. Schneider H.P. Deitmer J.W. Calcium release from intracellular stores in rodent astrocytes and neurons in situ.Cell Calcium. 2004; 35: 47-58Crossref PubMed Scopus (55) Google Scholar, Carmignoto et al., 1998Carmignoto G. Pasti L. Pozzan T. On the role of voltage-dependent calcium channels in calcium signaling of astrocytes in situ.J. Neurosci. 1998; 18: 4637-4645PubMed Google Scholar, Nett et al., 2002Nett W.J. Oloff S.H. McCarthy K.D. Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity.J. Neurophysiol. 2002; 87: 528-537PubMed Google Scholar, Parri and Crunelli, 2003Parri H.R. Crunelli V. The role of Ca2+ in the generation of spontaneous astrocytic Ca2+ oscillations.Neuroscience. 2003; 120: 979-992Crossref PubMed Scopus (70) Google Scholar, Porter and McCarthy, 1995bPorter J.T. McCarthy K.D. GFAP-positive hippocampal astrocytes in situ respond to glutamatergic neuroligands with increases in [Ca2+]i.Glia. 1995; 13: 101-112Crossref PubMed Google Scholar, Straub et al., 2006Straub S.V. Bonev A.D. Wilkerson M.K. Nelson M.T. Dynamic inositol trisphosphate-mediated calcium signals within astrocytic endfeet underlie vasodilation of cerebral arterioles.J. Gen. Physiol. 2006; 128: 659-669Crossref PubMed Scopus (35) Google Scholar). However, it remains possible that this alternate Ca2+ source could be important in the fine processes of astrocytes where it is difficult to study Ca2+ regulation. Overall, the field as a whole is only beginning to appreciate the complexity of signaling molecules activated when astrocytic Gq GPCRs are stimulated and how these molecules, together with Ca2+, shape the cellular response. In spite of the fact that astrocytic signaling has been studied for nearly three decades, very little is known concerning the role of astrocytic Gq GPCRs in neurophysiology. Our lack of progress in this area stems, in large part, from the difficulty in selectively activating or blocking astrocytic Gq GPCRs in situ or in vivo. Astroglial Ca2+ signaling can easily be assessed in vitro using purified cultured astroglia. However, most investigators in the field acknowledge that cultured astroglia present a very poor model for studying the functions of astrocytic Gq GPCRs in situ or in vivo. For example, the morphological characteristics of astrocytes in situ are lost in cultured astroglia. In addition, cultured astroglia express genes that are not necessarily expressed in vivo, favoring the concept of a "glial" cell class, while the gene profiles of different subpopulations of astrocytes are dissimilar in situ (Cahoy et al., 2008Cahoy J.D. Emery B. Kaushal A. Foo L.C. Zamanian J.L. Christopherson K.S. Xing Y. Lubischer J.L. Krieg P.A. Krupenko S.A. et al.A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function.J. Neurosci. 2008; 28: 264-278Crossref PubMed Scopus (679) Google Scholar, Lovatt et al., 2007Lovatt D. Sonnewald U. Waagepetersen H.S. Schousboe A. He W. Lin J.H. Han X. Takano T. Wang S. Sim F.J. et al.The transcriptome and metabolic gene signature of protoplasmic as
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