title: Astrocyte glutamate transporters regulate metabotropic glutamate receptor-mediated excitation of hippocampal interneurons.
abstract: Clearance of extracellular glutamate is essential for limiting the activity of metabotropic glutamate receptors (mGluRs) at excitatory synapses; however, the relative contribution of transporters found in neuronal and glial membranes to this uptake is poorly understood. Hippocampal interneurons located at the oriens-alveus border express mGluR1alpha, a metabotropic glutamate receptor that regulates excitability and synaptic plasticity. To determine which glutamate transporters are essential for removing glutamate at these excitatory synapses, we recorded mGluR1-mediated EPSCs from oriens-lacunosum moleculare (O-LM) interneurons in acute hippocampal slices. Stimulation in stratum oriens reliably elicited a slow mGluR1-mediated current in O-LM interneurons if they were briefly depolarized to allow Ca2+ entry before stimulation. Selective inhibition of GLT-1 [for glutamate transporter; EAAT2 (for excitatory amino acid transporter)] with dihydrokainate increased the amplitude of these responses approximately threefold, indicating that these transporters compete with mGluRs for synaptically released glutamate. However, inhibition of all glutamate transporters with TBOA (DL-threo-b-benzyloxyaspartic acid) increased mGluR1 EPSCs >15-fold, indicating that additional transporters also shape activation of these receptors. To identify these transporters, we examined mGluR1 EPSCs in mice lacking GLAST (for glutamate-aspartate transporter; EAAT1) or EAAC1 (for excitatory amino acid carrier; EAAT3). A comparison of responses recorded from wild-type and transporter knock-out mice revealed that the astroglial glutamate transporters GLT-1 and GLAST, but not the neuronal transporter EAAC1, restrict activation of mGluRs in O-LM interneurons. Transporter-dependent potentiation of mGluR1 EPSCs led to a dramatic increase in interneuron firing and enhanced inhibition of CA1 pyramidal neurons, suggesting that acute or prolonged disruption of transporter activity could lead to changes in network activity as a result of enhanced interneuron excitability.
authors.affiliation: Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Yanhua H
authors.initials: YH
authors.lastname: Huang
authors.forename: Saurabh R
authors.initials: SR
authors.lastname: Sinha
authors.forename: Kohichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: Dwight E
authors.initials: DE
authors.lastname: Bergles
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D050491:Glutamate Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D027322:Amino Acid Transport System X-AG; D018683:Excitatory Amino Acid Agents; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D018094:Receptors, Metabotropic Glutamate; C493399:Slc1a1 protein, mouse; C493396:Slc1a2 protein, mouse; C493393:Slc1a3 protein, mouse; D027981:Symporters; C104077:metabotropic glutamate receptor type 1; D002118:Calcium