PMID- 20569241 OWN - NLM STAT- MEDLINE DCOM- 20110204 LR - 20131121 IS - 1474-9726 (Electronic) IS - 1474-9718 (Linking) VI - 9 IP - 5 DP - 2010 Oct TI - Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats. PG - 722-35 LID - 10.1111/j.1474-9726.2010.00593.x [doi] AB - This study aims to determine whether the regulation of extracellular glutamate is altered during aging and its possible consequences on synaptic transmission and plasticity. A decrease in the expression of the glial glutamate transporters GLAST and GLT-1 and reduced glutamate uptake occur in the aged (24-27 months) Sprague-Dawley rat hippocampus. Glutamatergic excitatory postsynaptic potentials recorded extracellularly in ex vivo hippocampal slices from adult (3-5 months) and aged rats are depressed by DL-TBOA, an inhibitor of glutamate transporter activity, in an N-Methyl-d-Aspartate (NMDA)-receptor-dependent manner. In aged but not in young rats, part of the depressing effect of DL-TBOA also involves metabotropic glutamate receptor (mGluRs) activation as it is significantly reduced by the specific mGluR antagonist d-methyl-4-carboxy-phenylglycine (MCPG). The paired-pulse facilitation ratio, a functional index of glutamate release, is reduced by MCPG in aged slices to a level comparable to that in young rats both under control conditions and after being enhanced by DL-TBOA. These results suggest that the age-associated glutamate uptake deficiency favors presynaptic mGluR activation that lowers glutamate release. In parallel, 2 Hz-induced long-term depression is significantly decreased in aged animals and is fully restored by MCPG. All these data indicate a facilitated activation of extrasynaptic NMDAR and mGluRs in aged rats, possibly because of an altered distribution of glutamate in the extrasynaptic space. This in turn affects synaptic transmission and plasticity within the aged hippocampal CA1 network. CI - (c) 2010 The Authors Aging Cell (c) 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland. FAU - Potier, Brigitte AU - Potier B AD - Universite Paris Descartes, Centre de Psychiatrie et de Neurosciences, UMR, Paris, France. brigitte.potier@inserm.fr FAU - Billard, Jean-Marie AU - Billard JM FAU - Riviere, Sylvain AU - Riviere S FAU - Sinet, Pierre-Marie AU - Sinet PM FAU - Denis, Isabelle AU - Denis I FAU - Champeil-Potokar, Gaelle AU - Champeil-Potokar G FAU - Grintal, Barbara AU - Grintal B FAU - Jouvenceau, Anne AU - Jouvenceau A FAU - Kollen, Melanie AU - Kollen M FAU - Dutar, Patrick AU - Dutar P LA - eng PT - Journal Article DEP - 20100722 PL - England TA - Aging Cell JT - Aging cell JID - 101130839 RN - 0 (Excitatory Amino Acid Transporter 1) RN - 0 (Excitatory Amino Acid Transporter 2) RN - 0 (Receptors, Metabotropic Glutamate) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Slc1a3 protein, rat) RN - 0 (benzyloxyaspartate) RN - 30KYC7MIAI (Aspartic Acid) RN - 3KX376GY7L (Glutamic Acid) SB - IM MH - Aging MH - Animals MH - Aspartic Acid/pharmacology MH - Excitatory Amino Acid Transporter 1/biosynthesis/metabolism MH - Excitatory Amino Acid Transporter 2/biosynthesis/metabolism MH - Excitatory Postsynaptic Potentials/drug effects MH - Glutamic Acid/deficiency/*metabolism MH - Hippocampus/*cytology/metabolism MH - Oxidation-Reduction MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Metabotropic Glutamate/*metabolism MH - Receptors, N-Methyl-D-Aspartate/*metabolism MH - Structure-Activity Relationship MH - Synapses/drug effects/*metabolism MH - Synaptic Transmission/drug effects MH - Tissue Distribution EDAT- 2010/06/24 06:00 MHDA- 2011/02/05 06:00 CRDT- 2010/06/24 06:00 PHST- 2010/06/24 06:00 [entrez] PHST- 2010/06/24 06:00 [pubmed] PHST- 2011/02/05 06:00 [medline] AID - ACE593 [pii] AID - 10.1111/j.1474-9726.2010.00593.x [doi] PST - ppublish SO - Aging Cell. 2010 Oct;9(5):722-35. doi: 10.1111/j.1474-9726.2010.00593.x. Epub 2010 Jul 22.