title: Generation of slow network oscillations in the developing rat hippocampus after blockade of glutamate uptake.
abstract: Cell-surface glutamate transporters are essential for the proper function of early cortical networks because their dysfunction induces seizures in the newborn rat in vivo. We have now analyzed the consequences of their inhibition by DL-TBOA on the activity of the developing CA1 rat hippocampal network in vitro. DL-TBOA generated a pattern of recurrent depolarization with an onset and decay of several seconds' duration in interneurons and pyramidal cells. These slow network oscillations (SNOs) were mostly mediated by gamma-aminobutyric acid (GABA) in pyramidal cells and by GABA and N-methyl-D-aspartate (NMDA) receptors in interneurons. However, in both cell types SNOs were blocked by NMDA receptor antagonists, suggesting that their generation requires a glutamatergic drive. Moreover, in interneurons, SNOs were still generated after the blockade of NMDA-mediated synaptic currents with MK-801, suggesting that SNOs are expressed by the activation of extrasynaptic NMDA receptors. Long-lasting bath application of glutamate or NMDA failed to induce SNOs, indicating that they are generated by periodic but not sustained activation of NMDA receptors. In addition, SNOs were observed in interneurons recorded in slices with or without the strata pyramidale and oriens, suggesting that the glutamatergic drive may originate from the radiatum and pyramidale strata. We propose that in the absence of an efficient transport of glutamate, the transmitter diffuses in the extracellular space to activate extrasynaptic NMDA receptors preferentially present on interneurons that in turn activate other interneurons and pyramidal cells. This periodic neuronal coactivation may contribute to the generation of seizures when glutamate transport dysfunction is present.
authors.affiliation: Institut de Neurobiologie de la Méditerranée (INMED), Institut National de la Santé et de la Recherche Médicale U29 (INSERMU29), Université de la Méditerranée, Marseille, France.
authors.forename: Adriano Augusto
authors.initials: AA
authors.lastname: Cattani
authors.forename: Valérie Delphine
authors.initials: VD
authors.lastname: Bonfardin
authors.forename: Alfonso
authors.initials: A
authors.lastname: Represa
authors.forename: Yehezkel
authors.initials: Y
authors.lastname: Ben-Ari
authors.forename: Laurent
authors.initials: L
authors.lastname: Aniksztejn
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D018698:Glutamic Acid / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D019579:Neocortex / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D050496:Vesicular Glutamate Transport Proteins / Q000037:antagonists & inhibitors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D058785:GABA-A Receptor Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D050496:Vesicular Glutamate Transport Proteins; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid