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Specificity and Actions of an Arylaspartate Inhibitor of Glutamate Transport at the Schaffer Collateral-CA1 Pyramidal Cell Synapse

By Weinan Sun, Katie M. Hoffman, David C. Holley and Michael P. Kavanaugh

Abstract

In this study we characterized the pharmacological selectivity and physiological actions of a new arylaspartate glutamate transporter blocker, L-threo-ß-benzylaspartate (L-TBA). At concentrations up to 100 µM, L-TBA did not act as an AMPA receptor (AMPAR) or NMDA receptor (NMDAR) agonist or antagonist when applied to outside-out patches from mouse hippocampal CA1 pyramidal neurons. L-TBA had no effect on the amplitude of field excitatory postsynaptic potentials (fEPSPs) recorded at the Schaffer collateral-CA1 pyramidal cell synapse. Excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons were unaffected by L-TBA in the presence of physiological extracellular Mg2+ concentrations, but in Mg2+-free solution, EPSCs were significantly prolonged as a consequence of increased NMDAR activity. Although L-TBA exhibited approximately four-fold selectivity for neuronal EAAT3 over glial EAAT1/EAAT2 transporter subtypes expressed in Xenopus oocytes, the L-TBA concentration-dependence of the EPSC charge transfer increase in the absence of Mg2+ was the same in hippocampal slices from EAAT3 +/+ and EAAT3 −/− mice, suggesting that TBA effects were primarily due to block of glial transporters. Consistent with this, L-TBA blocked synaptically evoked transporter currents in CA1 astrocytes with a potency in accord with its block of heterologously expressed glial transporters. Extracellular recording in the presence of physiological Mg2+ revealed that L-TBA prolonged fEPSPs in a frequency-dependent manner by selectively increasing the NMDAR-mediated component of the fEPSP during short bursts of activity. The data indicate that glial glutamate transporters play a dominant role in limiting extrasynaptic transmitter diffusion and binding to NMDARs. Furthermore, NMDAR signaling is primarily limited by voltage-dependent Mg2+ block during low-frequency activity, while the relative contribution of transport increases during short bursts of higher frequency signaling

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3161057
Provided by: PubMed Central

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Citations

  1. (1994). Block of glutamate transporters potentiates postsynaptic excitation.
  2. (2002). Cooperation between independent hippocampal synapses is controlled by glutamate uptake.
  3. (2005). Effects of a novel glutamate transporter blocker, (2S, 3S)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (TFB-TBOA), on activities of hippocampal neurons.
  4. (1999). Enhancement of glutamate release uncovers spillover-mediated transmission by N-methyl-Daspartate receptors in the rat hippocampus.
  5. (1997). Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake.
  6. (1997). Glutamate transporter protein subtypes are expressed differentially during rat CNS development.
  7. (2007). Glutamate transporters: confining runaway excitation by shaping synaptic transmission.
  8. (1993). Glutamate uptake from the synaptic cleft does not shape the decay of the non-NMDA component of the synaptic current.
  9. (2001). Neuronal glutamate transporters limit activation of NMDA receptors by neurotransmitter spillover on CA1 pyramidal cells.
  10. (2009). Neuronal transporters regulate glutamate clearance, NMDA receptor activation, and synaptic plasticity in the hippocampus.
  11. (1993). The uptake inhibitor L-trans-PDC enhances responses to glutamate but fails to alter the kinetics of excitatory synaptic currents in the hippocampus.