title: Glial glutamate transporter and glutamine synthetase regulate GABAergic synaptic strength in the spinal dorsal horn.
abstract: Decreased GABAergic synaptic strength ('disinhibition') in the spinal dorsal horn is a crucial mechanism contributing to the development and maintenance of pathological pain. However, mechanisms leading to disinhibition in the spinal dorsal horn remain elusive. We investigated the role of glial glutamate transporters (GLT-1 and GLAST) and glutamine synthetase in maintaining GABAergic synaptic activity in the spinal dorsal horn. Electrically evoked GABAergic inhibitory post-synaptic currents (eIPSCs), spontaneous IPSCs (sIPSCs) and miniature IPSCs were recorded in superficial spinal dorsal horn neurons of spinal slices from young adult rats. We used (2S,3S)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (TFB-TBOA), to block both GLT-1 and GLAST and dihydrokainic acid to block only GLT-1. We found that blockade of both GLAST and GLT-1 and blockade of only GLT-1 in the spinal dorsal horn decreased the amplitude of GABAergic eIPSCs, as well as both the amplitude and frequency of GABAergic sIPSCs or miniature IPSCs. Pharmacological inhibition of glial glutamine synthetase had similar effects on both GABAergic eIPSCs and sIPSCs. We provided evidence demonstrating that the reduction in GABAergic strength induced by the inhibition of glial glutamate transporters is due to insufficient GABA synthesis through the glutamate-glutamine cycle between astrocytes and neurons. Thus, our results indicate that deficient glial glutamate transporters and glutamine synthetase significantly attenuate GABAergic synaptic strength in the spinal dorsal horn, which may be a crucial synaptic mechanism underlying glial-neuronal interactions caused by dysfunctional astrocytes in pathological pain conditions.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia, USA.
authors.forename: Enshe
authors.initials: E
authors.lastname: Jiang
authors.forename: Xisheng
authors.initials: X
authors.lastname: Yan
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D004558:Electric Stimulation; D055724:Electrophysiological Phenomena; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000502:physiology*; D005973:Glutamine / Q000494:pharmacology; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology*
chemical_list: C508240:(2S,3S)-3-(3-(4-(trifluoromethyl)benzoylamino)benzyloxy)aspartate; D027341:Excitatory Amino Acid Transporter 1; C493392:Slc1a3 protein, rat; D005973:Glutamine; D001224:Aspartic Acid; C020889:dihydrokainic acid; D005680:gamma-Aminobutyric Acid; D005974:Glutamate-Ammonia Ligase; D007608:Kainic Acid