Astrocyte dysfunction in epilepsy

Epilepsy comprises a group of disorders characterized by the periodic occurrence of seizures. Currently available anticonvulsant drugs and therapies are insufficient to controlling seizure activity in about one third of epilepsy patients. Thus, there is an urgent need for new therapies that prevent the genesis of the disorder and improve seizure control in individuals already afflicted. The vast majority of epileptic cases are of idiopathic origin, and a deeper understanding of the cellular basis of hyperactivity and synchronization is essential. Neurosurgical specimens from patients with temporal lobe epilepsy typically demonstrate marked reactive gliosis. Since recent studies have implicated astrocytes in important physiological roles in the CNS, such as synchronization of neuronal firing, it is plausible that they may also have a role in seizure generation or seizure spread. In support of this view, several membrane channels, receptors and transporters in the astrocytic membrane have been found to be deeply altered in the epileptic brain, and they are now gradually emerging as new potential targets for antiepileptic therapeutic strategies. This review summarizes current evidence regarding astroglial dysfunction in epilepsy and discusses presumed underlying mechanisms.

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

[2]  R. Nicoll,et al.  Excitatory Synaptic Transmission Persists Independently of the Glutamate–Glutamine Cycle , 2007, The Journal of Neuroscience.

[3]  C. Giaume,et al.  Glucose metabolism and proliferation in glia: role of astrocytic gap junctions , 2006, Journal of neurochemistry.

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

[5]  K. Inoki,et al.  Signaling by Target of Rapamycin Proteins in Cell Growth Control , 2005, Microbiology and Molecular Biology Reviews.

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

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

[8]  E. Aronica,et al.  Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex , 2001, Acta Neuropathologica.

[9]  P. Agre,et al.  Specialized Membrane Domains for Water Transport in Glial Cells: High-Resolution Immunogold Cytochemistry of Aquaporin-4 in Rat Brain , 1997, The Journal of Neuroscience.

[10]  D. Gutmann,et al.  The Natural History and Treatment of Epilepsy in a Murine Model of Tuberous Sclerosis , 2007, Epilepsia.

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

[12]  M. Hurme,et al.  Increased Plasma Levels of Pro‐ and Anti‐inflammatory Cytokines in Patients with Febrile Seizures , 2002, Epilepsia.

[13]  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.

[14]  L. Zeng,et al.  The Mammalian Target of Rapamycin Signaling Pathway Mediates Epileptogenesis in a Model of Temporal Lobe Epilepsy , 2009, The Journal of Neuroscience.

[15]  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.

[16]  C. Giaume,et al.  Cx43 Hemichannels and Gap Junction Channels in Astrocytes Are Regulated Oppositely by Proinflammatory Cytokines Released from Activated Microglia , 2007, The Journal of Neuroscience.

[17]  Maiken Nedergaard,et al.  Astrocytic glutamate release-induced transient depolarization and epileptiform discharges in hippocampal CA1 pyramidal neurons. , 2005, Journal of neurophysiology.

[18]  R. Ravid,et al.  Broad Expression of Toll‐Like Receptors in the Human Central Nervous System , 2002, Journal of neuropathology and experimental neurology.

[19]  Kun-Liang Guan,et al.  Dysregulation of the TSC-mTOR pathway in human disease , 2004, Nature Genetics.

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

[21]  M. Dragunow,et al.  Neurochemical and morphological changes associated with human epilepsy , 1995, Brain Research Reviews.

[22]  Amy L. Brewster,et al.  Fever, febrile seizures and epilepsy , 2007, Trends in Neurosciences.

[23]  E. Newman,et al.  Potassium buffering in the central nervous system , 2004, Neuroscience.

[24]  J. P. Dreier,et al.  Blood–brain barrier disruption results in delayed functional and structural alterations in the rat neocortex , 2007, Neurobiology of Disease.

[25]  G. Carmignoto,et al.  Enhanced Astrocytic Ca 2 + Signals Contribute to Neuronal Excitotoxicity after Status Epilepticus , 2010 .

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

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

[28]  C. Steinhäuser,et al.  Ion channels in glial cells , 2000, Brain Research Reviews.

[29]  Devin K. Binder,et al.  Analysis of Astroglial K+ Channel Expression in the Developing Hippocampus Reveals a Predominant Role of the Kir4.1 Subunit , 2009, The Journal of Neuroscience.

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

[31]  D. Boison.  The adenosine kinase hypothesis of epileptogenesis , 2008, Progress in Neurobiology.

[32]  F R Tang,et al.  Expression of the group II and III metabotropic glutamate receptors in the hippocampus of patients with mesial temporal lobe epilepsy , 2001, Journal of neurocytology.

[33]  P. Fisher,et al.  β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression , 2005, Nature.

[34]  T. Pozzan,et al.  Intracellular Calcium Oscillations in Astrocytes: A Highly Plastic, Bidirectional Form of Communication between Neurons and Astrocytes In Situ , 1997, The Journal of Neuroscience.

[35]  J. Hablitz,et al.  Functional expression of Kir4.1 channels in spinal cord astrocytes , 2006, Glia.

[36]  R. Koehler,et al.  Astrocytes and the regulation of cerebral blood flow , 2009, Trends in Neurosciences.

[37]  Ole P. Ottersen,et al.  Delayed K+ clearance associated with aquaporin-4 mislocalization: Phenotypic defects in brains of α-syntrophin-null mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Nedergaard,et al.  Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. , 1994, Science.

[39]  E. Audinat,et al.  Status Epilepticus Induces a Particular Microglial Activation State Characterized by Enhanced Purinergic Signaling , 2008, The Journal of Neuroscience.

[40]  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.

[41]  A. Reichenbach,et al.  Downregulation of Kir4.1 inward rectifying potassium channel subunits by RNAi impairs potassium transfer and glutamate uptake by cultured cortical astrocytes , 2007, Glia.

[42]  Michela Matteoli,et al.  Vesicular transmitter release from astrocytes , 2006, Glia.

[43]  R. D’Ambrosio,et al.  Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K(+) in rat hippocampus. , 2002, Journal of neurophysiology.

[44]  U. Heinemann,et al.  Blood–brain barrier breakdown-inducing astrocytic transformation: Novel targets for the prevention of epilepsy , 2009, Epilepsy Research.

[45]  Shigeyoshi Itohara,et al.  Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. , 2008, The Journal of clinical investigation.

[46]  Zhuan Zhou,et al.  “Kiss-and-Run” Glutamate Secretion in Cultured and Freshly Isolated Rat Hippocampal Astrocytes , 2005, The Journal of Neuroscience.

[47]  Geoffrey T Manley,et al.  Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin‐4 water channels , 2006, Glia.

[48]  F. Dudek,et al.  Update on connexins and gap junctions in neurons and glia in the mammalian nervous system , 2004, Brain Research Reviews.

[49]  H. Sontheimer,et al.  Cytokine modulation of glial glutamate uptake: a possble involvement of nitric oxide , 1996, Neuroreport.

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

[51]  Ruslan Medzhitov,et al.  Toll-like receptors and innate immunity , 2001, Nature Reviews Immunology.

[52]  P. V. van Rijen,et al.  Reduced glutamine synthetase in hippocampal areas with neuron loss in temporal lobe epilepsy , 2005, Neurology.

[53]  E. Benveniste,et al.  Immune function of astrocytes , 2001, Glia.

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

[55]  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.

[56]  G. Kollias,et al.  CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity , 2001, Nature Neuroscience.

[57]  M. Shapira,et al.  Transcriptome Profiling Reveals TGF-β Signaling Involvement in Epileptogenesis , 2009, The Journal of Neuroscience.

[58]  P. Mulholland,et al.  Glutamate Transporters Regulate Extrasynaptic NMDA Receptor Modulation of Kv2.1 Potassium Channels , 2008, The Journal of Neuroscience.

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

[60]  Y. Kurachi,et al.  An inwardly rectifying K(+) channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. , 2001, American journal of physiology. Cell physiology.

[61]  Frank Kirchhoff,et al.  Lack of the Kir4.1 channel subunit abolishes K+ buffering properties of astrocytes in the ventral respiratory group: impact on extracellular K+ regulation. , 2006, Journal of neurophysiology.

[62]  J. L. Stringer,et al.  Sodium pump activity, not glial spatial buffering, clears potassium after epileptiform activity induced in the dentate gyrus. , 2000, Journal of neurophysiology.

[63]  B. Engelhardt,et al.  Loss of astrocyte polarity marks blood–brain barrier impairment during experimental autoimmune encephalomyelitis , 2009, Acta Neuropathologica.

[64]  U. Heinemann,et al.  The Impact of Astrocytic Gap Junctional Coupling on Potassium Buffering in the Hippocampus , 2006, The Journal of Neuroscience.

[65]  Shuxian Hu,et al.  Cytokine Effects on Glutamate Uptake by Human Astrocytes , 2000, Neuroimmunomodulation.

[66]  J. Simard,et al.  Transforming Growth Factor-β1 Regulates Kir2.3 Inward Rectifier K+ Channels via Phospholipase C and Protein Kinase C-δ in Reactive Astrocytes from Adult Rat Brain* , 2002, The Journal of Biological Chemistry.

[67]  D. Spencer,et al.  Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[68]  T. Ploug,et al.  Excitatory amino acid transporters EAAT‐1 and EAAT‐2 in temporal lobe and hippocampus in intractable temporal lobe epilepsy , 2009, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[69]  P. V. van Rijen,et al.  Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. , 2002, Brain : a journal of neurology.

[70]  P. Fisher,et al.  Mechanism of Ceftriaxone Induction of Excitatory Amino Acid Transporter-2 Expression and Glutamate Uptake in Primary Human Astrocytes* , 2008, Journal of Biological Chemistry.

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

[72]  Jens P Dreier,et al.  Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex , 2004, The Journal of Neuroscience.

[73]  J. Hablitz,et al.  Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia , 2008, Neurobiology of Disease.

[74]  Carissa G. Fonseca,et al.  Upregulation in astrocytic connexin 43 gap junction levels may exacerbate generalized seizures in mesial temporal lobe epilepsy , 2002, Brain Research.

[75]  E. Aronica,et al.  Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. , 2007, Brain : a journal of neurology.

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

[77]  E. Aronica,et al.  Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins , 2003, The European journal of neuroscience.

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

[79]  A. Williamson,et al.  Glutamate and astrocytes—Key players in human mesial temporal lobe epilepsy? , 2008, Epilepsia.

[80]  C. Giaume,et al.  Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by β‐amyloid , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[81]  A. von Deimling,et al.  Effects of barium on stimulus‐induced rises of [K+]o in human epileptic non‐sclerotic and sclerotic hippocampal area CA1 , 2000, The European journal of neuroscience.

[82]  H. Lester,et al.  Genetic Inactivation of an Inwardly Rectifying Potassium Channel (Kir4.1 Subunit) in Mice: Phenotypic Impact in Retina , 2000, The Journal of Neuroscience.

[83]  P. V. van Rijen,et al.  Expression and Cell Distribution of Group I and Group II Metabotropic Glutamate Receptor Subtypes in Taylor‐type Focal Cortical Dysplasia , 2003, Epilepsia.

[84]  R. Dingledine,et al.  Astrocytes in the Epileptic Brain , 2008, Neuron.

[85]  R. Malenka,et al.  Control of synaptic strength by glial TNFalpha. , 2002, Science.

[86]  T. Fellin,et al.  Do astrocytes contribute to excitation underlying seizures? , 2005, Trends in molecular medicine.

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

[88]  Ole Petter Ottersen,et al.  An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[89]  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 .

[90]  Timothy A. Pedley,et al.  Epilepsy : a comprehensive textbook , 2008 .

[91]  Uwe Heinemann,et al.  Ceiling of stimulus induced rises in extracellular potassium concentration in the cerebral cortex of cat , 1977, Brain Research.

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

[93]  P. Buckmaster,et al.  Inhibition of the Mammalian Target of Rapamycin Signaling Pathway Suppresses Dentate Granule Cell Axon Sprouting in a Rodent Model of Temporal Lobe Epilepsy , 2009, The Journal of Neuroscience.

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

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

[96]  S. Akira,et al.  Toll-like receptors and innate immunity , 2006, Journal of Molecular Medicine.

[97]  Aaron,et al.  Altered expression of connexin subtypes in mesial temporal lobe epilepsy in humans. , 2006, Journal of neurosurgery.

[98]  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.

[99]  Ø. Skare,et al.  Expression of glutamine synthetase and glutamate dehydrogenase in the latent phase and chronic phase in the kainate model of temporal lobe epilepsy , 2008, Glia.

[100]  H. Zaveri,et al.  Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats. , 2008, Brain : a journal of neurology.

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

[102]  A. Vezzani,et al.  The role of cytokines in the pathophysiology of epilepsy , 2008, Brain, Behavior, and Immunity.

[103]  Charles B. Mikell,et al.  Tuberous sclerosis: A primary pathology of astrocytes? , 2008, Epilepsia.

[104]  Céline Dubé,et al.  Erratum: Interleukin-1β contributes to the generation of experimental febrile seizures (Annals of Neurology (January 2005) 57 (152-155)) , 2005 .

[105]  David L. Paul,et al.  Gap junction gene expression in human seizure disorder , 1991, Experimental Neurology.

[106]  Todd A Fiacco,et al.  What Is the Role of Astrocyte Calcium in Neurophysiology? , 2008, Neuron.

[107]  C. Steinhäuser,et al.  Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity. , 2002, European journal of pharmacology.

[108]  G. Ojemann,et al.  Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy , 1999, Neurology.

[109]  Michael Wong,et al.  Impaired astrocytic gap junction coupling and potassium buffering in a mouse model of tuberous sclerosis complex , 2009, Neurobiology of Disease.

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

[111]  P. Emson,et al.  Expression of the glutamate transporters in human temporal lobe epilepsy , 1999, Neuroscience.

[112]  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.

[113]  P. Carlen,et al.  Connexin 43 mimetic peptides inhibit spontaneous epileptiform activity in organotypic hippocampal slice cultures , 2008, Experimental Neurology.

[114]  R. Malenka,et al.  Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-α , 2005, The Journal of Neuroscience.

[115]  Noo Li Jeon,et al.  Presynaptic Regulation of Astroglial Excitatory Neurotransmitter Transporter GLT1 , 2009, Neuron.

[116]  Wade Morishita,et al.  Control of Synaptic Strength by Glial TNFα , 2002, Science.