Glutamate transporters and presynaptic metabotropic glutamate receptors protect neocortical Cajal-Retzius cells against over-excitation.
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, Mg(2+) blockade of NMDA receptors, and presynaptic mGluRs that inhibit transmission at GABAergic synapses.
Cluster of Excellence Neurocure, Department of Experimental Neurology, University Medicine Charitè, Robert-Koch-Platz 4, 10115, Berlin, Germany.
Anton
A
Dvorzhak
Petr
P
Unichenko
Sergei
S
Kirischuk
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D027341:Excitatory Amino Acid Transporter 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000166:cytology* / Q000502:physiology; D009433:Neural Inhibition; D009474:Neurons / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C508240:(2S,3S)-3-(3-(4-(trifluoromethyl)benzoylamino)benzyloxy)aspartate; D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C493396:Slc1a2 protein, mouse; C493393:Slc1a3 protein, mouse; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid