The tripartite synapse: roles for gliotransmission in health and disease.

In addition to being essential supporters of neuronal function, astrocytes are now recognized as active elements in the brain. Astrocytes sense and integrate synaptic activity and, depending on intracellular Ca(2+) levels, release gliotransmitters (e.g. glutamate, d-serine and ATP) that have feedback actions on neurons. Recent experimental results have raised the possibility that quantitative variations in gliotransmission might contribute to disorders of the nervous system. Here, we discuss targeted molecular genetic approaches that have demonstrated that alterations in protein expression in astrocytes can lead to serious changes in neuronal function. We also introduce the concept of 'astrocyte activation spectrum' in which enhanced and reduced gliotransmission might contribute to epilepsy and schizophrenia, respectively. The results of future experimental tests of the astrocyte activation spectrum, which relates gliotransmission to neurological and psychiatric disorders, might point to a new therapeutic target in the brain.

[1]  S. W. Kuffler,et al.  Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. , 1966, Journal of neurophysiology.

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

[3]  T. Takano,et al.  Intercellular calcium signaling mediated by point-source burst release of ATP , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[5]  Maiken Nedergaard,et al.  Astrocyte-mediated activation of neuronal kainate receptors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  T. Komori,et al.  Tau‐positive dial Inclusions in Progressive Supranuclear Palsy, Corticobasal Degeneration and Pick's Disease , 1999, Brain pathology.

[7]  B. Moghaddam,et al.  NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[8]  R. Malenka,et al.  Synaptic scaling mediated by glial TNF-α , 2006, Nature.

[9]  T. Jones,et al.  Rapid laminar-dependent changes in GFAP immunoreactive astrocytes in the visual cortex of rats reared in a complex environment , 1996, Psychoneuroendocrinology.

[10]  M. Landt,et al.  Analysis of Cerebrospinal Fluid Glial Fibrillary Acidic Protein after Seizures in Children , 2003, Epilepsia.

[11]  S. Snyder,et al.  D-Serine as a putative glial neurotransmitter. , 2004, Neuron glia biology.

[12]  Harald Sontheimer,et al.  Properties of human glial cells associated with epileptic seizure foci , 1998, Epilepsy Research.

[13]  S. Finkbeiner,et al.  Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. , 1990, Science.

[14]  J. Trojanowski,et al.  Transgenic Mouse Model of Tau Pathology in Astrocytes Leading to Nervous System Degeneration , 2005, The Journal of Neuroscience.

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

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

[17]  P. Haydon,et al.  Calcium-Dependent Exocytosis of Atrial Natriuretic Peptide from Astrocytes , 2003, The Journal of Neuroscience.

[18]  Tullio Pozzan,et al.  Prostaglandins stimulate calcium-dependent glutamate release in astrocytes , 1998, Nature.

[19]  H. Kimelberg,et al.  ATP regulates anion channel-mediated organic osmolyte release from cultured rat astrocytes via multiple Ca2+-sensitive mechanisms. , 2005, American journal of physiology. Cell physiology.

[20]  K N Sheth,et al.  Purification of serine racemase: biosynthesis of the neuromodulator D-serine. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

[22]  A. Charles,et al.  Intercellular signaling in glial cells: Calcium waves and oscillations in response to mechanical stimulation and glutamate , 1991, Neuron.

[23]  J. Kleinman,et al.  Glial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia , 2005, Neuroscience.

[24]  S. Koizumi,et al.  Spatial and temporal aspects of Ca2+ signaling mediated by P2Y receptors in cultured rat hippocampal astrocytes. , 2002, Life sciences.

[25]  G. Rajkowska,et al.  Layer-specific reductions in GFAP-reactive astroglia in the dorsolateral prefrontal cortex in schizophrenia , 2002, Schizophrenia Research.

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

[27]  Christian Steinhäuser,et al.  Astrocyte dysfunction in neurological disorders: a molecular perspective , 2006, Nature Reviews Neuroscience.

[28]  J. Coyle,et al.  Glutamatergic mechanisms in schizophrenia. , 2003, Annual review of pharmacology and toxicology.

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

[30]  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.

[31]  Peter Lipton,et al.  Do active cerebral neurons really use lactate rather than glucose? , 2001, Trends in Neurosciences.

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

[33]  R. Roth,et al.  The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia , 1999, Neuropsychopharmacology.

[34]  R. Yolken,et al.  Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder , 2000, Molecular Psychiatry.

[35]  F. Sams-Dodd.  Phencyclidine‐induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia , 1996, Behavioural pharmacology.

[36]  E. Newman.  New roles for astrocytes: Regulation of synaptic transmission , 2003, Trends in Neurosciences.

[37]  Pierre J. Magistretti,et al.  Cellular bases of functional brain imaging: insights from neuron-glia metabolic coupling 1 1 Published on the World Wide Web on 12 October 2000. , 2000, Brain Research.

[38]  T. Takano,et al.  An astrocytic basis of epilepsy , 2005, Nature Medicine.

[39]  A. Hodgkin,et al.  Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo , 1952, The Journal of physiology.

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

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

[42]  B. Roth,et al.  Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗ ∗ See accompanying Editorial, in this issue. , 1999, Biological Psychiatry.

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

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

[45]  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.

[46]  W. Walz.  Role of astrocytes in the clearance of excess extracellular potassium , 2000, Neurochemistry International.

[47]  Elena Kartvelishvily,et al.  Neuron-derived D-Serine Release Provides a Novel Means to Activate N-Methyl-D-aspartate Receptors* , 2006, Journal of Biological Chemistry.

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

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

[50]  H. Sontheimer,et al.  Spontaneous intracellular calcium oscillations in cortical astrocytes from a patient with intractable childhood epilepsy (Rasmussen's Encephalitis) , 1997, Glia.

[51]  O. Ottersen,et al.  Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy , 2004, The Lancet.

[52]  J. Trojanowski,et al.  Expression of the small heat-shock protein alphaB-crystallin in tauopathies with glial pathology. , 2004, The American journal of pathology.

[53]  Peter Saggau,et al.  Adenosine inhibits evoked synaptic transmission primarily by reducing presynaptic calcium influx in area CA1 of hippocampus , 1994, Neuron.

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

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

[56]  Nicholas Lange,et al.  D-serine added to antipsychotics for the treatment of schizophrenia , 1998, Biological Psychiatry.

[57]  J. Wegiel,et al.  Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease , 2004, Neurobiology of Aging.

[58]  Jullie W Pan,et al.  Mesial temporal lobe epilepsy: a proton magnetic resonance spectroscopy study and a histopathological analysis. , 2004, Journal of neurosurgery.

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

[60]  M. Poo,et al.  Contribution of astrocytes to hippocampal long-term potentiation through release of d-serine , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[61]  R Y Tsien,et al.  New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures. , 1980, Biochemistry.

[62]  Pierre J Magistretti,et al.  Neuron-glia metabolic coupling and plasticity. , 2006, The Journal of experimental biology.

[63]  S. Iversen,et al.  The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. , 1989, European journal of pharmacology.

[64]  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.

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

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

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

[68]  C. Elger,et al.  Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances , 2000, The European journal of neuroscience.

[69]  V. Tennyson.  The Fine Structure of the Nervous System. , 1970 .

[70]  T. Fellin,et al.  Astrocytes coordinate synaptic networks: balanced excitation and inhibition. , 2006, Physiology.

[71]  C. Jahr,et al.  Glial Contribution to Glutamate Uptake at Schaffer Collateral–Commissural Synapses in the Hippocampus , 1998, The Journal of Neuroscience.

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

[73]  F. Kirchhoff,et al.  Astroglial processes show spontaneous motility at active synaptic terminals in situ , 2004, The European journal of neuroscience.

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

[75]  Masahiko Watanabe,et al.  Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. , 1997, Science.

[76]  K. Do,et al.  Glutamate-induced homocysteic acid release from astrocytes: possible implication in glia-neuron signaling , 2004, Neuroscience.

[77]  M. Fink,et al.  Meduna and the origins of convulsive therapy. , 1984, The American journal of psychiatry.

[78]  F. Kirchhoff,et al.  Segregated Expression of AMPA-Type Glutamate Receptors and Glutamate Transporters Defines Distinct Astrocyte Populations in the Mouse Hippocampus , 2003, The Journal of Neuroscience.

[79]  A. Levey,et al.  Selective loss of glial glutamate transporter GLT‐1 in amyotrophic lateral sclerosis , 1995, Annals of neurology.

[80]  Maiken Nedergaard,et al.  Astrocyte-mediated control of cerebral microcirculation , 2003, Trends in Neurosciences.

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

[82]  K. McCarthy,et al.  Hippocampal Astrocytes In Situ Respond to Glutamate Released from Synaptic Terminals , 1996, The Journal of Neuroscience.

[83]  A. Cornell-Bell,et al.  Human epileptic astrocytes exhibit increased gap junction coupling , 1995, Glia.

[84]  Christian Giaume,et al.  Control of gap-junctional communication in astrocytic networks , 1996, Trends in Neurosciences.

[85]  Ultrahigh-speed photochemical stimulation of neurons , 2005, Nature Methods.

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

[87]  G. Collingridge,et al.  Excitatory amino acids in synaptic transmission in the Schaffer collateral‐commissural pathway of the rat hippocampus. , 1983, The Journal of physiology.

[88]  Greg Miller,et al.  The Dark Side of Glia , 2005, Science.

[89]  A. Meister,et al.  Identification of L-methionine-S-sulfoximine as the convulsant isomer of methionine sulfoximine. , 1970, Proceedings of the National Academy of Sciences of the United States of America.

[90]  L. Eng,et al.  Glial Fibrillary Acidic Protein: GFAP-Thirty-One Years (1969–2000) , 2000, Neurochemical Research.