Inhibition of GABA uptake in the rat hippocampal slice |
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| Authors: | Stephen J. Korn Raymond Dingledine |
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| Affiliation: | 1. Inserm, Inserm UMR-S U1237, Université de Caen-Normandie, GIP Cyceron, Boulevard H. Becquerel, Caen, France;2. Normandie Université, UNICAEN, PSL Research University, EPHE, Inserm, U1077, CHU de Caen, Neuropsychologie et Imagerie de la Mémoire Humaine, Caen, France;3. Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, NeuroCure Clinical Research Center, Berlin, Germany;4. Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Stroke Research Berlin, Berlin, Germany;1. Gordon Center for Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;2. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA;3. Department of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women''s Hospital, Harvard Medical School, Boston, MA, USA;4. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;1. Graduate Program in Medicine and Health Sciences School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil;2. Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil;3. Laboratory of Neuroscience Brain Institute (BraIns) of Rio Grande do Sul, Porto Alegre, Brazil;4. Preclinical Research Center, Brain Institute (BraIns) of Rio Grande do Sul, Porto Alegre, Brazil;5. Department of Biochemistry Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil;6. Department of Pharmacology Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil;7. Graduate Program in Biological Sciences: Biochemistry Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil;8. Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil;1. Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria;2. Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria;3. Center for Biomarker Research in Medicine (CBmed), Graz, Austria;4. Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria |
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| Abstract: | Pharmacological manipulations known to inhibit GABA uptake prolonged GABA-evoked conductance increases in CA1 pyramidal cells in the rat hippocampal slice preparation. Treatments included reduction of extracellular sodium and exposure to cis-4-OH-nipecotic acid, nipecotic acid or L-2,4-diaminobutyric acid (all at 1 mM). These effects contrast with the results obtained with 4-OH-isonipecotic acid, an inactive structural analog of nipecotic acid, which had no effect on the time-course of GABA responses. 4,5,6,7-Tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THPO), an impotent but selective inhibitor of GABA uptake into glia, did not prolong GABA-evoked responses. The effect of sodium reduction depended on the distance between the source of GABA and its receptors, as predicted for an uptake-limited response. GABA-receptor agonists that are poor substrates for GABA uptake (muscimol, thiomuscimol, piperidine-4-sulphonic acid, isoguvacine and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP) evoked very long conductance changes that were not further prolonged by uptake inhibitors. These results demonstrate the presence of a functional GABA uptake system in the hippocampal slice. The accessibility of hippocampal GABAergic synapses and the known susceptibility of the hippocampus to epileptiform events suggest that the hippocampal slice could be a valuable CNS preparation to study the role of GABA uptake in synaptic physiology. |
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| Keywords: | hippocampus hippocampal slice γ -aminobutyric acid epilepsy GABA uptake GABA receptor agonist cis-4-hydroxy-nipecotic acid 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THPO) |
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