Enhancement of AMPA-Mediated Current after Traumatic Injury in Cortical Neurons

Overactivation of ionotropic glutamate receptors has been implicated in the pathophysiology of traumatic brain injury. Using an in vitro cell injury model, we examined the effects of stretch-induced traumatic injury on the AMPA subtype of ionotropic glutamate receptors in cultured neonatal cortical neurons. Recordings made using the whole-cell patch-clamp technique revealed that a subpopulation of injured neurons exhibited an increased current in response to AMPA. The current–voltage relationship of these injured neurons showed an increased slope conductance but no change in reversal potential compared with uninjured neurons. Additionally, the EC50 values of uninjured and injured neurons were nearly identical. Thus, current potentiation was not caused by changes in the voltage-dependence, ion selectivity, or apparent agonist affinity of the AMPA channel. AMPA-elicited current could also be fully inhibited by the application of selective AMPA receptor antagonists, thereby excluding the possibility that current potentiation in injured neurons was caused by the activation of other, nondesensitizing receptors. The difference in current densities between control and injured neurons was abolished when AMPA receptor desensitization was inhibited by the coapplication of AMPA and cyclothiazide or by the use of kainate as an agonist, suggesting that mechanical injury alters AMPA receptor desensitization. Reduction of AMPA receptor desensitization after brain injury would be expected to further exacerbate the effects of increased postinjury extracellular glutamate and contribute to trauma-related cell loss and dysfunctional synaptic information processing.

[1]  H. Hatt.  Modification of Glutamate Receptor Channels: Molecular Mechanisms and Functional Consequences , 1999, Naturwissenschaften.

[2]  R. Dingledine,et al.  The glutamate receptor ion channels. , 1999, Pharmacological reviews.

[3]  D. Graham,et al.  The neuronal cytoskeleton is at risk after mild and moderate brain injury. , 1998, Journal of neurotrauma.

[4]  E. Ottow,et al.  ZK200775: a phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Trojanowski,et al.  gThe Dorothy Russell Memorial Lecture* The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms , 1998, Neuropathology and applied neurobiology.

[6]  G. Lynch,et al.  The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization , 1998, Brain Research.

[7]  Gary Lynch,et al.  AMPA receptor desensitization modulates synaptic responses induced by repetitive afferent stimulation in hippocampal slices , 1998, Brain Research.

[8]  A. Schousboe,et al.  Ampa receptor mediated excitotoxicity in neocortical neurons is developmentally regulated and dependent upon receptor desensitization , 1998, Neurochemistry International.

[9]  N. Matsumoto,et al.  Characterization of cyclothiazide-enhanced kainate excitotoxicity in rat hippocampal cultures , 1998, Neurochemistry International.

[10]  T. Soderling,et al.  Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. , 1997, Science.

[11]  S. J. Tavalin,et al.  Inhibition of the electrogenic Na pump underlies delayed depolarization of cortical neurons after mechanical injury or glutamate. , 1997, Journal of neurophysiology.

[12]  L. Satin,et al.  Reduction of Voltage-Dependent Mg2+ Blockade of NMDA Current in Mechanically Injured Neurons , 1996, Science.

[13]  B. Ballyk,et al.  Activity of 2,3-benzodiazepines at Native Rat and Recombinant Human Glutamate Receptors In Vitro: Stereospecificity and Selectivity Profiles , 1996, Neuropharmacology.

[14]  D. W. McBride,et al.  The pharmacology of mechanogated membrane ion channels. , 1996, Pharmacological reviews.

[15]  L. Turski,et al.  Traumatic brain damage prevented by the non-N-methyl-D-aspartate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f] quinoxaline. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  D Colquhoun,et al.  Deactivation and desensitization of non‐NMDA receptors in patches and the time course of EPSCs in rat cerebellar granule cells. , 1996, The Journal of physiology.

[17]  E. Ellis,et al.  Stretch-induced injury of cultured neuronal, glial, and endothelial cells. Effect of polyethylene glycol-conjugated superoxide dismutase. , 1996, Stroke.

[18]  W. Steers,et al.  Protein kinase C in cyclic stretch-induced nerve growth factor production by urinary tract smooth muscle cells. , 1995, The American journal of physiology.

[19]  J. Povlishock,et al.  A new model for rapid stretch-induced injury of cells in culture: characterization of the model using astrocytes. , 1995, Journal of neurotrauma.

[20]  R. Busto,et al.  Widespread metabolic depression and reduced somatosensory circuit activation following traumatic brain injury in rats. , 1994, Journal of neurotrauma.

[21]  P. Ascher,et al.  Mechanosensitivity of NMDA receptors in cultured mouse central neurons , 1994, Neuron.

[22]  J. Hablitz,et al.  Altered desensitization produces enhancement of EPSPs in neocortical neurons. , 1994, Journal of neurophysiology.

[23]  L. Wang,et al.  Modulation of AMPA/kainate receptors in cultured murine hippocampal neurones by protein kinase C. , 1994, The Journal of physiology.

[24]  D. Marion,et al.  Traumatic Brain Injury‐Induced Excitotoxicity Assessed in a Controlled Cortical Impact Model , 1993, Journal of neurochemistry.

[25]  B. Sakmann,et al.  Action of brief pulses of glutamate on AMPA/kainate receptors in patches from different neurones of rat hippocampal slices. , 1992, The Journal of physiology.

[26]  B Sakmann,et al.  Glutamate receptor channels in isolated patches from CA1 and CA3 pyramidal cells of rat hippocampal slices. , 1992, The Journal of physiology.

[27]  I. Raman,et al.  The kinetics of the response to glutamate and kainate in neurons of the avian cochlear nucleus , 1992, Neuron.

[28]  Li Chen,et al.  Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation , 1992, Nature.

[29]  B. Sakmann,et al.  The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits , 1992, Neuron.

[30]  J. Povlishock,et al.  Traumatically Induced Reactive Change as Visualized Through the Use of Monoclonal Antibodies Targeted to Neurofilament Subunits , 1992, Journal of neuropathology and experimental neurology.

[31]  M. Mayer,et al.  Modulation of excitatory synaptic transmission by drugs that reduce desensitization at AMPA/kainate receptors , 1991, Neuron.

[32]  P. Greengard,et al.  Enhancement of the glutamate response by cAMP-dependent protein kinase in hippocampal neurons , 1991, Science.

[33]  M. Salter,et al.  Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases , 1991, Science.

[34]  M. Mayer,et al.  Kinetic analysis of interactions between kainate and AMPA: Evidence for activation of a single receptor in mouse hippocampal neurons , 1991, Neuron.

[35]  D. Hovda,et al.  Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. , 1990, Journal of neurosurgery.

[36]  G. Clifton,et al.  Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat , 1990, Brain Research.

[37]  D. Clifford,et al.  Blockade of desensitization augments quisqualate excitotoxicity in hippocampal neurons , 1990, Neuron.

[38]  S. Ozawa,et al.  Permeation of calcium through excitatory amino acid receptor channels in cultured rat hippocampal neurones. , 1990, The Journal of physiology.

[39]  M. Goldberg,et al.  Non-NMDA receptor-mediated neurotoxicity in cortical culture , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[40]  L. Noble,et al.  Traumatic brain injury in the rat: Characterization of a lateral fluid-percussion model , 1989, Neuroscience.

[41]  G. Collingridge,et al.  Excitatory amino acid receptors in the vertebrate central nervous system. , 1989, Pharmacological reviews.

[42]  R. Vink,et al.  The role of excitatory amino acids and NMDA receptors in traumatic brain injury. , 1989, Science.

[43]  M. Dichter,et al.  Quisqualate activates a rapidly inactivating high conductance ionic channel in hippocampal neurons. , 1989, Science.

[44]  S N Davies,et al.  Quinoxalinediones: potent competitive non-NMDA glutamate receptor antagonists. , 1988, Science.

[45]  M. Mayer,et al.  The physiology of excitatory amino acids in the vertebrate central nervous system , 1987, Progress in Neurobiology.

[46]  A. Kriegstein,et al.  Glutamate neurotoxicity in cortical cell culture , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[47]  D. Choi.  Ionic dependence of glutamate neurotoxicity , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[48]  J. Olney,et al.  Glutamate and the pathophysiology of hypoxic–ischemic brain damage , 1986, Annals of neurology.

[49]  O. Krishtal,et al.  Excitatory amino acid receptors in hippocampal neurons: Kainate fails to desensitize them , 1986, Neuroscience Letters.

[50]  H. Benveniste,et al.  Elevation of the Extracellular Concentrations of Glutamate and Aspartate in Rat Hippocampus During Transient Cerebral Ischemia Monitored by Intracerebral Microdialysis , 1984, Journal of neurochemistry.

[51]  R. Bullock,et al.  Glutamate release and cerebral blood flow after severe human head injury. , 1996, Acta neurochirurgica. Supplement.

[52]  J. Povlishock,et al.  Traumatically induced axonal damage: evidence for enduring changes in axolemmal permeability with associated cytoskeletal change. , 1996, Acta neurochirurgica. Supplement.

[53]  S. Heinemann,et al.  Cloned glutamate receptors. , 1994, Annual review of neuroscience.

[54]  E. Costa,et al.  Modulation of AMPA/kainate receptors by analogues of diazoxide and cyclothiazide in thin slices of rat hippocampus. , 1993, Receptors & channels.

[55]  R. Hayes,et al.  Cognitive deficits following traumatic brain injury produced by controlled cortical impact. , 1992, Journal of neurotrauma.

[56]  L. Trussell,et al.  Rapid desensitization of glutamate receptors in vertebrate central neurons. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[57]  R. Vink,et al.  Changes in cellular bioenergetic state following graded traumatic brain injury in rats: determination by phosphorus 31 magnetic resonance spectroscopy. , 1988, Journal of neurotrauma.

[58]  G. Clifton,et al.  Pretreatment with phencyclidine, an N-methyl-D-aspartate antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury. , 1988, Journal of neurotrauma.