title: Glutamate transport blockade has a differential effect on AMPA and NMDA receptor-mediated synaptic transmission in the developing barrel cortex.
abstract: High affinity glutamate transport plays an important role in maintaining a low extracellular glutamate concentration in the CNS. Excitotoxicity due to a loss of glutamate transporter function has been implicated in disease processes such as stroke and amyotrophic lateral sclerosis (ALS). We studied the effects of glutamate transport inhibitors on thalamocortical synapses at developing (postnatal day 3-8) layer IV neurons in the barrel cortex using the thalamocortical slice preparation and whole-cell recordings. Inhibition of glutamate transport by D,L-threo-beta-hydroxyaspartate (THA), a combination of THA and dihydrokainate (DHK), or by L-trans-pyrrolidine-2,4-dicarboxylate (tPDC), caused a reversible blockade of AMPA and kainate receptor-mediated dual component excitatory postsynaptic currents (AMPA/KA EPSCs). This effect was not blocked by cyclothiazide (CTZ) indicating that is was not due to desensitisation of AMPARs. Under conditions in which NMDA receptors were unblocked the transport inhibitors caused the massive activation of NMDA receptors leading to the rapid loss of recordings. Previous studies using these transport inhibitors on brain slices from older animals reported no or only modest effects on synaptic transmission. Therefore the data in the present study suggest that neurons in the developing neocortex are particularly sensitive to glutamate transporter function. Furthermore the effects of transport inhibition are dependent upon whether neurons are sufficiently depolarised to relieve the voltage-dependent block of NMDA receptors.
authors.affiliation: MRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol, UK.
authors.forename: F L
authors.initials: FL
authors.lastname: Kidd
authors.forename: J T
authors.initials: JT
authors.lastname: Isaac
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004232:Diuretics; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000493:pharmacokinetics; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D013003:Somatosensory Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013788:Thalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D001224:Aspartic Acid; D001581:Benzothiadiazines; D003998:Dicarboxylic Acids; D004232:Diuretics; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018698:Glutamic Acid; D007608:Kainic Acid; D014179:Neurotransmitter Uptake Inhibitors; D010852:Picrotoxin; D011759:Pyrrolidines; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D049993:Sodium Chloride Symporter Inhibitors; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C011274:3-hydroxyaspartic acid; C020889:dihydrokainic acid; C083486:pyrrolidine-2,4-dicarboxylic acid; C004639:cyclothiazide