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Glutamate transporters and presynaptic metabotropic glutamate receptors protect neocortical Cajal–Retzius cells against over-excitation

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Abstract

Cajal–Retzius (CR) cells, early generated neurons in the marginal zone of developing neocortex, are reported to be highly vulnerable to excitotoxic damage. Because extracellular glutamate concentration in the central nervous system is mainly controlled by glutamate transporters (EAATs), we studied the effects of EAAT blockade on CR cells. dl-TBOA, a specific EAAT antagonist, induced NMDA receptor-dependent bursting discharges in layer 2/3 pyramidal neurons, indicating that EAATs operate in the uptake mode and their blockade leads to elevation of extracellular glutamate concentration. In CR cells, however, dl-TBOA failed to change either the membrane resistance or holding current, and moreover, it reduced the frequency of spontaneous GABAergic postsynaptic currents. dl-TBOA decreased the mean amplitude and increased paired-pulse ratio of evoked GABAergic postsynaptic currents, indicating the presynaptic locus of its action. Indeed, LY379268, a specific agonist of group II metabotropic glutamate receptors (mGluR-II), mimicked the dl-TBOA-mediated effects, and LY341495, an unspecific mGluR antagonist, eliminated the dl-TBOA-induced effects. As dihydrokainic acid, a specific EAAT2 blocker, failed to affect evoked GABAergic postsynaptic currents, whereas TFB-TBOA, a selective blocker of EAAT1 and EAAT2, produced effects similar to that of dl-TBOA, extracellular glutamate concentration in the marginal zone is mainly controlled by EAAT1 (GLAST). Thus, even though CR cells are highly vulnerable to excitotoxic damage, a number of mechanisms serve to protect them against excessive extracellular glutamate concentration including a lack of functional glutamatergic synapses, Mg2+ blockade of NMDA receptors, and presynaptic mGluRs that inhibit transmission at GABAergic synapses.

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Acknowledgments

The technical assistance of Mrs. Kerstin Rückwardt is highly appreciated. This study was supported by Deutsche Forschungsgemeinschaft (KI1093/1-2 to SK) and by Stiftung Rheinland-Pfalz für Innovation (961-386261/955 to SK). We thank Dr. Werner Kilb and Prof. Heiko Luhmann for the helpful discussion.

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Authors and Affiliations

  1. Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany

    Petr Unichenko & Sergei Kirischuk

  2. Cluster of Excellence Neurocure, Department of Experimental Neurology University Medicine Charitè, Robert-Koch-Platz 4, 10115, Berlin, Germany

    Anton Dvorzhak

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  1. Anton Dvorzhak
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Correspondence to Sergei Kirischuk.

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Dvorzhak, A., Unichenko, P. & Kirischuk, S. Glutamate transporters and presynaptic metabotropic glutamate receptors protect neocortical Cajal–Retzius cells against over-excitation. Pflugers Arch - Eur J Physiol 464, 217–225 (2012). https://doi.org/10.1007/s00424-012-1109-8

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