Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior.

The past decade has seen an explosion of research on roles of neuron-astrocyte interactions in the control of brain function. We highlight recent studies performed on the tripartite synapse, the structure consisting of pre- and postsynaptic elements of the synapse and an associated astrocytic process. Astrocytes respond to neuronal activity and neurotransmitters, through the activation of metabotropic receptors, and can release the gliotransmitters ATP, d-serine, and glutamate, which act on neurons. Astrocyte-derived ATP modulates synaptic transmission, either directly or through its metabolic product adenosine. d-serine modulates NMDA receptor function, whereas glia-derived glutamate can play important roles in relapse following withdrawal from drugs of abuse. Cell type-specific molecular genetics has allowed a new level of examination of the function of astrocytes in brain function and has revealed an important role of these glial cells that is mediated by adenosine accumulation in the control of sleep and in cognitive impairments that follow sleep deprivation.

[1]  K. Behar,et al.  Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole , 2010, Molecular Psychiatry.

[2]  Jessica A. Cardin,et al.  Driving fast-spiking cells induces gamma rhythm and controls sensory responses , 2009, Nature.

[3]  K. Deisseroth,et al.  Parvalbumin neurons and gamma rhythms enhance cortical circuit performance , 2009, Nature.

[4]  Murtaza Z Mogri,et al.  Optical Deconstruction of Parkinsonian Neural Circuitry , 2009, Science.

[5]  C. Colton,et al.  Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer's disease , 2009, Neuroscience.

[6]  G. Mandel,et al.  Non–cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology , 2009, Nature Neuroscience.

[7]  B. Hyman,et al.  Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer Mice , 2009, Science.

[8]  Michael M. Halassa,et al.  Astrocytic Modulation of Sleep Homeostasis and Cognitive Consequences of Sleep Loss , 2009, Neuron.

[9]  Yevgeniy B. Sirotin,et al.  Anticipatory haemodynamic signals in sensory cortex not predicted by local neuronal activity. , 2009, Nature.

[10]  Ralph Lydic,et al.  Adenosine A1 and A2A Receptors in Mouse Prefrontal Cortex Modulate Acetylcholine Release and Behavioral Arousal , 2009, The Journal of Neuroscience.

[11]  T. Stone,et al.  Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. , 2009, Handbook of experimental pharmacology.

[12]  Nathalie Rouach,et al.  Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission , 2008, Science.

[13]  B. Barres The Mystery and Magic of Glia: A Perspective on Their Roles in Health and Disease , 2008, Neuron.

[14]  J. Schrader,et al.  Distribution of ectonucleotidases in the rodent brain revisited , 2008, Cell and Tissue Research.

[15]  W. Singer,et al.  The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. , 2008, Schizophrenia bulletin.

[16]  G. Buzsáki,et al.  A neural coding scheme formed by the combined function of gamma and theta oscillations. , 2008, Schizophrenia bulletin.

[17]  J. Poulet,et al.  Internal brain state regulates membrane potential synchrony in barrel cortex of behaving mice , 2008, Nature.

[18]  G. Tononi,et al.  Is Sleep Essential? , 2008, PLoS biology.

[19]  Martin Oheim,et al.  Lysosomes Are the Major Vesicular Compartment Undergoing Ca2+-Regulated Exocytosis from Cortical Astrocytes , 2008, The Journal of Neuroscience.

[20]  V. Murthy,et al.  Coupling of Neural Activity to Blood Flow in Olfactory Glomeruli Is Mediated by Astrocytic Pathways , 2008, Neuron.

[21]  E. Shigetomi,et al.  Two Forms of Astrocyte Calcium Excitability Have Distinct Effects on NMDA Receptor-Mediated Slow Inward Currents in Pyramidal Neurons , 2008, The Journal of Neuroscience.

[22]  H. Berg,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S7 Tables S1 to S3 References Movies S1 to S6 Tuned Responses of Astrocytes and Their Influence on Hemodynamic Signals in the Visual Cortex , 2022 .

[23]  Vladimir Parpura,et al.  Ca2+ entry through TRPC1 channels contributes to intracellular Ca2+ dynamics and consequent glutamate release from rat astrocytes , 2008, Glia.

[24]  Keisuke Sawada,et al.  Identification of a vesicular nucleotide transporter , 2008, Proceedings of the National Academy of Sciences.

[25]  Harald Sontheimer,et al.  A role for glutamate in growth and invasion of primary brain tumors , 2008, Journal of neurochemistry.

[26]  A. Araque,et al.  Endocannabinoids Mediate Neuron-Astrocyte Communication , 2008, Neuron.

[27]  Takahiro Takano,et al.  Loss of Astrocytic Domain Organization in the Epileptic Brain , 2008, The Journal of Neuroscience.

[28]  Magdalena Götz,et al.  Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain , 2008, Proceedings of the National Academy of Sciences.

[29]  P. Carmeliet,et al.  Protective Role of Reactive Astrocytes in Brain Ischemia , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[30]  Weida Tong,et al.  Reproducible and reliable microarray results through quality control: good laboratory proficiency and appropriate data analysis practices are essential. , 2008, Current opinion in biotechnology.

[31]  G. Tononi,et al.  Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep , 2008, Nature Neuroscience.

[32]  Y. Xing,et al.  A Transcriptome Database for Astrocytes, Neurons, and Oligodendrocytes: A New Resource for Understanding Brain Development and Function , 2008, The Journal of Neuroscience.

[33]  P. Kotagal,et al.  The relationship between sleep and epilepsy. , 2001, Seminars in pediatric neurology.

[34]  Hideyuki Okano,et al.  A dual role for reactive astrocytes after spinal cord injury , 2007, Neuroscience Research.

[35]  Sean L. Hill,et al.  Sleep homeostasis and cortical synchronization: I. Modeling the effects of synaptic strength on sleep slow waves. , 2007, Sleep.

[36]  S. Goldman,et al.  The Transcriptome and Metabolic Gene Signature of Protoplasmic Astrocytes in the Adult Murine Cortex , 2007, The Journal of Neuroscience.

[37]  K. McCarthy,et al.  Conditional Knock-Out of Kir4.1 Leads to Glial Membrane Depolarization, Inhibition of Potassium and Glutamate Uptake, and Enhanced Short-Term Synaptic Potentiation , 2007, The Journal of Neuroscience.

[38]  G. Carmignoto,et al.  Enhanced Astrocytic Ca2+ Signals Contribute to Neuronal Excitotoxicity after Status Epilepticus , 2007, The Journal of Neuroscience.

[39]  M. Freire,et al.  Cajal's contributions to glia research , 2007, Trends in Neurosciences.

[40]  B. MacVicar,et al.  Astrocyte control of the cerebrovasculature , 2007, Glia.

[41]  Qingming Luo,et al.  Regulated ATP release from astrocytes through lysosome exocytosis , 2007, Nature Cell Biology.

[42]  Michael M. Halassa,et al.  Synaptic Islands Defined by the Territory of a Single Astrocyte , 2007, The Journal of Neuroscience.

[43]  C. J. Lee,et al.  Astrocytic control of synaptic NMDA receptors , 2007, The Journal of physiology.

[44]  Todd A Fiacco,et al.  Selective Stimulation of Astrocyte Calcium In Situ Does Not Affect Neuronal Excitatory Synaptic Activity , 2007, Neuron.

[45]  G. Sanacora,et al.  GABAergic contributions to the pathophysiology of depression and the mechanism of antidepressant action. , 2007, CNS & neurological disorders drug targets.

[46]  Khaleel Bhaukaurally,et al.  Glutamate exocytosis from astrocytes controls synaptic strength , 2007, Nature Neuroscience.

[47]  B. Conklin,et al.  Development of Hydrocephalus in Mice Expressing the Gi-Coupled GPCR Ro1 RASSL Receptor in Astrocytes , 2007, The Journal of Neuroscience.

[48]  David F. Meaney,et al.  mGluR5 stimulates gliotransmission in the nucleus accumbens , 2007, Proceedings of the National Academy of Sciences.

[49]  Michael M. Halassa,et al.  The tripartite synapse: roles for gliotransmission in health and disease. , 2007, Trends in molecular medicine.

[50]  Tsutomu Hashikawa,et al.  Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95–neuroligin , 2007, Nature Neuroscience.

[51]  T. Hashimoto,et al.  Deciphering the disease process of schizophrenia: the contribution of cortical GABA neurons. , 2007, International review of neurobiology.

[52]  Inhibition and timing in cortical neural circuits. , 2007, The American journal of psychiatry.

[53]  Eduardo D. Martín,et al.  Adenosine released by astrocytes contributes to hypoxia‐induced modulation of synaptic transmission , 2007, Glia.

[54]  M. Sofroniew,et al.  Essential protective roles of reactive astrocytes in traumatic brain injury. , 2006, Brain : a journal of neurology.

[55]  S. Gobbo,et al.  Astrocytic Glutamate Is Not Necessary for the Generation of Epileptiform Neuronal Activity in Hippocampal Slices , 2006, The Journal of Neuroscience.

[56]  M. Haber,et al.  Cooperative Astrocyte and Dendritic Spine Dynamics at Hippocampal Excitatory Synapses , 2006, The Journal of Neuroscience.

[57]  D. Coulter,et al.  Dynamic Regulation of Synaptic GABA Release by the Glutamate-Glutamine Cycle in Hippocampal Area CA1 , 2006, The Journal of Neuroscience.

[58]  Hideyuki Okano,et al.  Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury , 2006, Nature Medicine.

[59]  P. Magistretti Neuron–glia metabolic coupling and plasticity , 2006, Journal of Experimental Biology.

[60]  T. Takano,et al.  Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo , 2006, Nature Neuroscience.

[61]  Philippe Hantraye,et al.  Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate Handling In Vivo , 2006, The Journal of Neuroscience.

[62]  S. Oliet,et al.  Glia-Derived d-Serine Controls NMDA Receptor Activity and Synaptic Memory , 2006, Cell.

[63]  J. Lacaille,et al.  GABAergic Network Activation of Glial Cells Underlies Hippocampal Heterosynaptic Depression , 2006, The Journal of Neuroscience.

[64]  Eric A Newman,et al.  Glial Cells Dilate and Constrict Blood Vessels: A Mechanism of Neurovascular Coupling , 2006, The Journal of Neuroscience.

[65]  T. Takano,et al.  Astrocyte-mediated control of cerebral blood flow , 2006, Nature Neuroscience.

[66]  G. Tononi,et al.  Sleep function and synaptic homeostasis. , 2006, Sleep medicine reviews.

[67]  D. Contreras,et al.  Balanced Excitation and Inhibition Determine Spike Timing during Frequency Adaptation , 2006, The Journal of Neuroscience.

[68]  A. Butt,et al.  Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions , 2006, Journal of cellular and molecular medicine.

[69]  M. Haber,et al.  Reshaping neuron-glial communication at hippocampal synapses. , 2005, Neuron glia biology.

[70]  R. Myers,et al.  Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[71]  Cathryn L. Kubera,et al.  Astrocytic Purinergic Signaling Coordinates Synaptic Networks , 2005, Science.

[72]  M. Sofroniew,et al.  Reactive Astrocytes in Neural Repair and Protection , 2005, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[73]  Grant R. Gordon,et al.  Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy , 2005, Nature Neuroscience.

[74]  J. Meldolesi,et al.  Astrocytes, from brain glue to communication elements: the revolution continues , 2005, Nature Reviews Neuroscience.

[75]  Eric A Newman,et al.  Calcium Increases in Retinal Glial Cells Evoked by Light-Induced Neuronal Activity , 2005, The Journal of Neuroscience.

[76]  Loredano Pollegioni,et al.  Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[77]  K. Willecke,et al.  Emerging complexities in identity and function of glial connexins , 2005, Trends in Neurosciences.

[78]  S. Gobbo,et al.  Neuronal Synchrony Mediated by Astrocytic Glutamate through Activation of Extrasynaptic NMDA Receptors , 2005, Neuron.

[79]  J. Tiihonen,et al.  Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis , 2005, Schizophrenia Research.

[80]  Leif Hertz,et al.  Astrocytic control of glutamatergic activity: astrocytes as stars of the show , 2004, Trends in Neurosciences.

[81]  J. Filosa,et al.  Calcium Dynamics in Cortical Astrocytes and Arterioles During Neurovascular Coupling , 2004, Circulation research.

[82]  B. MacVicar,et al.  Calcium transients in astrocyte endfeet cause cerebrovascular constrictions , 2004, Nature.

[83]  M. C. Angulo,et al.  Glutamate Released from Glial Cells Synchronizes Neuronal Activity in the Hippocampus , 2004, The Journal of Neuroscience.

[84]  Robert W. McCarley,et al.  Adenosine and sleep–wake regulation , 2004, Progress in Neurobiology.

[85]  Mitsunori Fukuda,et al.  Synaptotagmin IV regulates glial glutamate release. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[86]  V. Gundersen,et al.  Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate , 2004, Nature Neuroscience.

[87]  Michael M. Halassa,et al.  Fusion-related Release of Glutamate from Astrocytes* , 2004, Journal of Biological Chemistry.

[88]  V. Parpura,et al.  Vesicular Glutamate Transporter-Dependent Glutamate Release from Astrocytes , 2004, Journal of Neuroscience.

[89]  Ngan B. Doan,et al.  Reactive Astrocytes Protect Tissue and Preserve Function after Spinal Cord Injury , 2004, The Journal of Neuroscience.

[90]  Todd A Fiacco,et al.  Intracellular Astrocyte Calcium Waves In Situ Increase the Frequency of Spontaneous AMPA Receptor Currents in CA1 Pyramidal Neurons , 2004, The Journal of Neuroscience.

[91]  A. Schousboe Pharmacological and Functional Characterization of Astrocytic GABA Transport: A Short Review , 2000, Neurochemical Research.

[92]  Mu-ming Poo,et al.  ATP Released by Astrocytes Mediates Glutamatergic Activity-Dependent Heterosynaptic Suppression , 2003, Neuron.

[93]  T. Takano,et al.  Signaling at the Gliovascular Interface , 2003, The Journal of Neuroscience.

[94]  R. Lempicki,et al.  Evaluation of gene expression measurements from commercial microarray platforms. , 2003, Nucleic acids research.

[95]  P. Kalivas,et al.  Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse , 2003, Nature Neuroscience.

[96]  B. Ransom,et al.  Functional Hemichannels in Astrocytes: A Novel Mechanism of Glutamate Release , 2003, The Journal of Neuroscience.

[97]  Eric A Newman,et al.  Glial Cell Inhibition of Neurons by Release of ATP , 2003, The Journal of Neuroscience.

[98]  S. Duan,et al.  P2X7 Receptor-Mediated Release of Excitatory Amino Acids from Astrocytes , 2003, The Journal of Neuroscience.

[99]  M. Matteoli,et al.  Storage and Release of ATP from Astrocytes in Culture* , 2003, The Journal of Biological Chemistry.

[100]  M. C. Angulo,et al.  Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation , 2003, Nature Neuroscience.

[101]  D. Copenhagen,et al.  The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[102]  H. Bading,et al.  Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways , 2002, Nature Neuroscience.

[103]  J. Cloix,et al.  In vivo and in vitro glycogenic effects of methionine sulfoximine are different in two inbred strains of mice , 2002, Brain Research.

[104]  Mark Ellisman,et al.  Protoplasmic Astrocytes in CA1 Stratum Radiatum Occupy Separate Anatomical Domains , 2002, The Journal of Neuroscience.

[105]  Emma J. Blott,et al.  Secretory lysosomes , 2002, Nature Reviews Molecular Cell Biology.

[106]  J. Storm-Mathisen,et al.  The Expression of Vesicular Glutamate Transporters Defines Two Classes of Excitatory Synapse , 2001, Neuron.

[107]  H. Parri,et al.  Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation , 2001, Nature Neuroscience.

[108]  C. Pariante,et al.  Glial cell abnormalities in major psychiatric disorders: the evidence and implications , 2001, Brain Research Bulletin.

[109]  D Chollet,et al.  The Homeostatic Regulation of Sleep Need Is under Genetic Control , 2001, The Journal of Neuroscience.

[110]  P. Haydon Glia: listening and talking to the synapse , 2001, Nature Reviews Neuroscience.

[111]  E. Newman Calcium signaling in retinal glial cells and its effect on neuronal activity. , 2001, Progress in brain research.

[112]  R. Swanson,et al.  Astrocyte glutamate transport: Review of properties, regulation, and physiological functions , 2000, Glia.

[113]  E. Lapouble,et al.  Correlation between brain glycogen and convulsive state in mice submitted to methionine sulfoximine. , 2000, Life sciences.

[114]  R. McCarley,et al.  Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study , 2000, Neuroscience.

[115]  R. Fremeau,et al.  Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. , 2000, Science.

[116]  D. Linden,et al.  D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[117]  The frontiers of sleep , 1999, Trends in Neurosciences.

[118]  K. Harris,et al.  Three-Dimensional Relationships between Hippocampal Synapses and Astrocytes , 1999, The Journal of Neuroscience.

[119]  Clive N Svendsen,et al.  Leukocyte Infiltration, Neuronal Degeneration, and Neurite Outgrowth after Ablation of Scar-Forming, Reactive Astrocytes in Adult Transgenic Mice , 1999, Neuron.

[120]  A. Araque,et al.  Tripartite synapses: glia, the unacknowledged partner , 1999, Trends in Neurosciences.

[121]  A. Malafosse,et al.  Genetic determinants of sleep regulation in inbred mice. , 1999, Sleep.

[122]  D. Attwell,et al.  Modulation of extracellular glutamate concentration in rat brain slices by cystine‐glutamate exchange , 1999, The Journal of physiology.

[123]  S. B. Kater,et al.  ATP Released from Astrocytes Mediates Glial Calcium Waves , 1999, The Journal of Neuroscience.

[124]  S. K. Malhotra,et al.  Reactive astrocytes: cellular and molecular cues to biological function , 1997, Trends in Neurosciences.

[125]  R. McCarley,et al.  Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. , 1997, Science.

[126]  F. Jursky,et al.  Developmental Expression of the Glycine Transporters GLYT1 and GLYT2 in Mouse Brain , 1996, Journal of neurochemistry.

[127]  P. Magistretti,et al.  Metabolic coupling between glia and neurons , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[128]  O. Manzoni,et al.  Metabotropic Glutamate Receptors Inhibiting Excitatory Synapses in the CA1 Area of Rat Hippocampus , 1995, The European journal of neuroscience.

[129]  S. Snyder,et al.  D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[130]  D. Pleasure,et al.  Inhibition of Astrocyte Glutamine Production by α‐Ketoisocaproic Acid , 1994 .

[131]  Fang Liu,et al.  Glutamate-mediated astrocyte–neuron signalling , 1994, Nature.

[132]  D. Pleasure,et al.  Inhibition of astrocyte glutamine production by alpha-ketoisocaproic acid. , 1994, Journal of neurochemistry.

[133]  Pierre J. Magistretti,et al.  Characterization of the glycogenolysis elicited by vasoactive intestinal peptide, noradrenaline and adenosine in primary cultures of mouse cerebral cortical astrocytes , 1991, Brain Research.

[134]  Alexander A. Borbély,et al.  Sleep homeostasis in the rat: Simulation of the time course of EEG slow-wave activity , 1991, Neuroscience Letters.

[135]  I Tobler,et al.  Sleep deprivation in rats: effects on EEG power spectra, vigilance states, and cortical temperature. , 1991, The American journal of physiology.

[136]  D. Attwell,et al.  Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake , 1990, Nature.

[137]  S. Higman,et al.  Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[138]  A. Borbély A two process model of sleep regulation. , 1982, Human neurobiology.