title: Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats.
abstract: 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.
authors.affiliation: Université Paris Descartes, Centre de Psychiatrie et de Neurosciences, UMR, Paris, France. brigitte.potier@inserm.fr
authors.forename: Brigitte
authors.initials: B
authors.lastname: Potier
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Billard
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rivière
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Sinet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denis
authors.forename: Gaelle
authors.initials: G
authors.lastname: Champeil-Potokar
authors.forename: Barbara
authors.initials: B
authors.lastname: Grintal
authors.forename: Anne
authors.initials: A
authors.lastname: Jouvenceau
authors.forename: Melanie
authors.initials: M
authors.lastname: Kollen
authors.forename: Patrick
authors.initials: P
authors.lastname: Dutar
mesh_terms: D000375:Aging; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000096:biosynthesis / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000172:deficiency / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C493392:Slc1a3 protein, rat; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid