Regenerative Glutamate Release by Presynaptic NMDA Receptors Contributes to Spreading Depression

Spreading depression (SD) is a slowly propagating neuronal depolarization that underlies certain neurologic conditions. The wave-like pattern of its propagation suggests that SD arises from an unusual form of neuronal communication. We used enzyme-based glutamate electrodes to show that during SD induced by transiently raising extracellular K+ concentrations ([K+]o) in rat brain slices, there was a rapid increase in the extracellular glutamate concentration that required vesicular exocytosis but unlike fast synaptic transmission, still occurred when voltage-gated sodium and calcium channels (VGSC and VGCC) were blocked. Instead, presynaptic N-methyl-D-aspartate (NMDA) receptors (NMDARs) were activated during SD and could generate substantial glutamate release to support regenerative glutamate release and propagating waves when VGSCs and VGCCs were blocked. In calcium-free solutions, high [K+]o still triggered SD-like waves and glutamate efflux. Under such a condition, glutamate release was blocked by mitochondrial Na+/Ca2+ exchanger inhibitors that likely blocked calcium release from mitochondria secondary to NMDA-induced Na+ influx. Therefore presynaptic NMDA receptor activation is sufficient for triggering vesicular glutamate release during SD via both calcium entry and release from mitochondria by mitochondrial Na+/Ca2+ exchanger. Our observations suggest that presynaptic NMDARs contribute to a cycle of glutamate-induced glutamate release that mediate high [K+]o-triggered SD.

[1]  W. Baumgartner,et al.  Mitochondrial Ca2+ mobilization is a key element in olfactory signaling , 2012, Nature Neuroscience.

[2]  M. Moskowitz,et al.  Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the α1A subunit of P/Q type calcium channels , 1999, Neuroscience.

[3]  Jens P Dreier,et al.  Preliminary Evidence That Ketamine Inhibits Spreading Depolarizations in Acute Human Brain Injury , 2009, Stroke.

[4]  N. Schoppa,et al.  Dendritic processing within olfactory bulb circuits , 2003, Trends in Neurosciences.

[5]  Mirko Santello,et al.  Gliotransmission and the tripartite synapse. , 2012, Advances in experimental medicine and biology.

[6]  Rosario Rizzuto,et al.  Mitochondria as sensors and regulators of calcium signalling , 2012, Nature Reviews Molecular Cell Biology.

[7]  R. Nicoll,et al.  Effects of reduced vesicular filling on synaptic transmission in rat hippocampal neurones , 2000, The Journal of physiology.

[8]  J. Dreier.  The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease , 2011, Nature Medicine.

[9]  D. Spray,et al.  P2X7 receptor-Pannexin1 complex: pharmacology and signaling. , 2008, American journal of physiology. Cell physiology.

[10]  M. Ferrari,et al.  Enhanced Excitatory Transmission at Cortical Synapses as the Basis for Facilitated Spreading Depression in CaV2.1 Knockin Migraine Mice , 2009, Neuron.

[11]  S. Lipton,et al.  NR3A-containing NMDARs promote neurotransmitter release and spike timing–dependent plasticity , 2011, Nature Neuroscience.

[12]  E. Fedele,et al.  Mechanisms of glutamate release elicited in rat cerebrocortical nerve endings by ‘pathologically’ elevated extraterminal K+ concentrations , 2007, Journal of neurochemistry.

[13]  P. Gout,et al.  The x  c− cystine/glutamate antiporter: A potential target for therapy of cancer and other diseases , 2008, Journal of cellular physiology.

[14]  M. Lauritzen,et al.  Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  D. Feldman,et al.  Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity , 2008, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[16]  Jason B. Castro,et al.  Subthreshold Glutamate Release from Mitral Cell Dendrites , 2009, The Journal of Neuroscience.

[17]  Y. Iwao,et al.  Relationships between glutamate release, blood flow and spreading depression: real-time monitoring using an electroenzymatic dialysis electrode , 1998, Neuroscience Research.

[18]  V. Shoshan-Barmatz,et al.  NCLX is an essential component of mitochondrial Na+/Ca2+ exchange , 2009, Proceedings of the National Academy of Sciences.

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

[20]  T. Chenevert,et al.  Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. , 1994, Journal of neurosurgery.

[21]  Jens P Dreier,et al.  Spreading depolarizations have prolonged direct current shifts and are associated with poor outcome in brain trauma. , 2011, Brain : a journal of neurology.

[22]  D. Attwell,et al.  Glutamate release in severe brain ischaemia is mainly by reversed uptake , 2000, Nature.

[23]  Brian A MacVicar,et al.  Transient swelling, acidification, and mitochondrial depolarization occurs in neurons but not astrocytes during spreading depression. , 2010, Cerebral cortex.

[24]  T. Südhof.  The Presynaptic Active Zone , 2012, Neuron.

[25]  Ulrich Dirnagl,et al.  Increased Extracellular K+ Concentration Reduces the Efficacy of N-methyl-d-aspartate Receptor Antagonists to Block Spreading Depression-Like Depolarizations and Spreading Ischemia , 2005, Stroke.

[26]  B. MacVicar,et al.  Multiple types of calcium channels in acutely isolated rat neostriatal neurons , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  L. Nowak,et al.  Magnesium gates glutamate-activated channels in mouse central neurones , 1984, Nature.

[28]  R. North,et al.  NMDA Receptors Mediate Neuron-to-Glia Signaling in Mouse Cortical Astrocytes , 2006, The Journal of Neuroscience.

[29]  D. Attwell,et al.  Modulation of non-vesicular glutamate release by pH , 1996, Nature.

[30]  Mark H Ellisman,et al.  The Micro-Architecture of Mitochondria at Active Zones: Electron Tomography Reveals Novel Anchoring Scaffolds and Cristae Structured for High-Rate Metabolism , 2010, The Journal of Neuroscience.

[31]  H. Monyer,et al.  Pharmacological properties of homomeric and heteromeric pannexin hemichannels expressed in Xenopus oocytes , 2005, Journal of neurochemistry.

[32]  M. Cataldi,et al.  Role of the mitochondrial sodium/calcium exchanger in neuronal physiology and in the pathogenesis of neurological diseases , 2009, Progress in Neurobiology.

[33]  D. Spray,et al.  P2X7 receptor-Pannexin1 complex: Pharmacology and signaling (American Journal of Physiology - Cell Physiology (2008) 295, (C752-C760) DOI 10.1152/ajpcell.00228.2008) , 2009 .

[34]  D. Spray,et al.  P 2 X 7 receptor-Pannexin 1 complex : pharmacology and signaling , 2008 .

[35]  P. Donnelly,et al.  Presynaptic NMDARs in the Hippocampus Facilitate Transmitter Release at Theta Frequency , 2010, Neuron.

[36]  O. Hubschmann,et al.  Cortical cellular response in acute subarachnoid hemorrhage. , 1980, Journal of neurosurgery.

[37]  G. Somjen.  Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. , 2001, Physiological reviews.

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

[39]  G. Shepherd,et al.  Three-Dimensional Structure and Composition of CA3→CA1 Axons in Rat Hippocampal Slices: Implications for Presynaptic Connectivity and Compartmentalization , 1998, The Journal of Neuroscience.

[40]  R. David Andrew,et al.  Imaging Spreading Depression and Associated Intracellular Calcium Waves in Brain Slices , 1998, The Journal of Neuroscience.

[41]  D. Attwell,et al.  Neurotransmitter depletion by bafilomycin is promoted by vesicle turnover , 2007, Neuroscience Letters.

[42]  K. Sano,et al.  Changes in extracellular potassium concentration in cortex and brain stem during the acute phase of experimental closed head injury. , 1981, Journal of neurosurgery.

[43]  R. Vandenberg,et al.  Distinct Conformational States Mediate the Transport and Anion Channel Properties of the Glutamate Transporter EAAT-1* , 2002, The Journal of Biological Chemistry.

[44]  M. Chesler,et al.  Extracellular pH changes and accompanying cation shifts during ouabain-induced spreading depression. , 2000, Journal of neurophysiology.

[45]  Peter G. Aitken,et al.  Membrane currents in CA1 pyramidal cells during spreading depression (SD) and SD-like hypoxic depolarization , 1993, Brain Research.

[46]  G. Paxinos.  The Rat nervous system , 1985 .

[47]  A. Urbani,et al.  Role of different voltage-gated Ca2+ channels in cortical spreading depression: Specific requirement of P/Q-type Ca2+ channels , 2011, Channels.

[48]  C. Shuttleworth,et al.  Zn2+ Influx Is Critical for Some Forms of Spreading Depression in Brain Slices , 2008, The Journal of Neuroscience.