Astrocyte Glutamate Transporters Regulate Metabotropic Glutamate Receptor-Mediated Excitation of Hippocampal Interneurons

• Published in: The Journal of neuroscience 2004-05, Vol.24 (19), p.4551-4559
• Main Authors: Huang, Yanhua H, Sinha, Saurabh R, Tanaka, Kohichi, Rothstein, Jeffrey D, Bergles, Dwight E
• Format: Article
• Language: English
• Subjects: Amino Acid Transport System X-AG - antagonists & inhibitors; Amino Acid Transport System X-AG - genetics; Amino Acid Transport System X-AG - metabolism; Animals; Astrocytes - metabolism; Calcium - metabolism; Cellular/Molecular; Electric Stimulation; Excitatory Amino Acid Agents - pharmacology; Excitatory Amino Acid Transporter 1; Excitatory Amino Acid Transporter 2; Excitatory Amino Acid Transporter 3; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Glutamate Plasma Membrane Transport Proteins; Hippocampus - cytology; Hippocampus - metabolism; In Vitro Techniques; Interneurons - drug effects; Interneurons - metabolism; Mice; Mice, Knockout; Neuronal Plasticity - physiology; Patch-Clamp Techniques; Pyramidal Cells - drug effects; Pyramidal Cells - metabolism; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - metabolism; Symporters - genetics; Symporters - metabolism; Synaptic Transmission - drug effects; Synaptic Transmission - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.5217-03.2004

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.