Role of uptake inγ-aminobutyric acid (GABA)-mediated responses in guinea pig hippocampal neurons
Intracellular recordings were obtained from hippocampal pyramidal neurons maintainedin vitro. Measurements were made of the conductance change induced by iontophoretically appliedγ-aminobutyric acid (GABA) and, using voltage-clamp techniques, of inhibitory postsynaptic currents resulting from activation of inhibitory pathways.
Analysis of GABA iontophoretic charge-response curves indicated that there was considerable variation among neurons with respect to the slope of this relation.
The placement of the GABA-containing pipette did not appear to be responsible for the observed variation, since vertical repositioning of the pipette did not alter the slope of the charge-response relationship.
Steady iontophoresis of GABA from one barrel of a double-barreled pipette markedly affected the charge-response relation obtained when short pulses were applied to the other barrel. The curve was shifted to the left, and the slope was decreased. Concomitantly, the enhanced GABA-induced responses were prolonged.
Similar alterations in GABA responsiveness were observed when the uptake blocker, nipecotic acid, was iontophoretically applied. Furthermore, bath application of saline containing a reduced sodium concentration (25% of control) also produced a prolongation of GABA-mediated responses.
Under voltage clamp, inhibitory postsynaptic currents were observed to have biphasic decays. The initial, fast decay was prolonged by an average of 18% by nipecotic acid, whereas the later, slow phase was prolonged by 23%.
The results of these studies support the hypothesis that a saturable GABA uptake system is responsible for the observed variation in the charge-response curves and, in turn, underlies the apparent sensitizing effect of excess GABA application. The results also suggest that a reduction of transmitter uptake affects the time course of inhibitory postsynaptic currents in the hippocampus.
Key wordshippocampus γ-aminobutyric acid (GABA) uptake inhibitory postsynaptic currents (IPSCs)
Unable to display preview. Download preview PDF.
- Aickin, C. C., and Deisz, R. A. (1981). Pentobarbitone interference with inhibitory synaptic transmission in crayfish stretch receptor neurones.J. Physiol. (Lond.)315175–187.Google Scholar
- Albers, R. W., and Brady, A. O. (1959). The distribution of glutamate decarboxylase in the nervous system of the rhesus monkey.J. Biol. Chem. 234926–928.Google Scholar
- Andersen, P., Dingledine, R., Gjerstad, L., Langmoen, I. A., and Mosfeldt Laursen, A. (1980). Two different responses of hippocampal pyramidal cells to application of gamma-amino butyric acid.J. Physiol. (Lond.)305279–296.Google Scholar
- Ben-Ari, Y., Krnjevic, K., Reiffenstein, R. J., and Reinhart, W. (1981). Inhibitory conductance changes and action of GABA in rat hippocampus.Neuroscience 62445–2463.Google Scholar
- Biscoe, T. J., and Straughan, D. W. (1966). Micro-electrophoretic studies of neurones in the cat hippocampus.J. Physiol. (Lond.)183341–359.Google Scholar
- Brown, D. A., and Galvan, M. (1977). Influence of neuroglial transport on the action ofγ-aminobutyric acid on mammalian ganglion cells.Br. J. Pharmacol. 59373–378.Google Scholar
- Brown, D. A., Collins, G. G. S., and Galvan, M. (1980). Influence of cellular transport on the interaction of amino acids withγ-aminobutyric acid (GABA)-receptors in the isolated olfactory cortex of the guinea pig.Br. J. Pharmacol. 68251–262.Google Scholar
- Clark, R. B., Gration, K. A. F., and Usherwood, P. N. R. (1980). Influence of glutamate and aspartate on time course of decay of excitatory synaptic currents at locust neuromuscular junctions.Brain Res. 192205–216.Google Scholar
- Collingridge, G. L., Gage, P. W., and Robertson, B. (1984). Inhibitory postsynaptic currents in rat hippocampal CA1 neurones.J. Physiol. (Lond.)356551–564.Google Scholar
- Crawford, A. C., and McBurney, R. N. (1977). The synergistic action of L-glutamate and L-aspartate at crustacean excitatory neuromuscular junctions.J. Physiol. (Lond.)268697–709.Google Scholar
- Curtis, D. R., and Lodge, D. (1977). Central actions of amino-oxyacetic acid.Brain Res. 129181–182.Google Scholar
- Curtis, D. R., Game, C. J. A., and Lodge, D. (1976). Thein vivo inactivation of GABA and other inhibitory amino acids in the cat nervous system.Exp. Brain Res. 25413–428.Google Scholar
- Deisz, R. A., and Dose, M. (1983). Comparison of GABA analogues at the crayfish stretch receptor neurone.Brain Res. Bull. 11283–288.Google Scholar
- DeLean, A., Munson, P. J., and Rodbard, D. (1978). Simultaneous analysis of families of sigmoidal curves: Application to bioassay, radioligand assay, and physiological dose-response curves.Am. J. Physiol. 235E97-E102.Google Scholar
- Djorup, A., Jahnsen, J., and Mosfeldt Laursen, A. (1981). The dendritic response to GABA in CA1 of the hippocampal slice.Brain Res. 219196–201.Google Scholar
- Dudel, J. (1975). Kinetics of postsynaptic action of glutamate pulses applied iontophoretically through high resistance micropipettes.Pfluegers Arch. 356329–346.Google Scholar
- Enna, S. J., and Snyder, S. H. (1975). Properties ofγ-aminobutyric acid (GABA) receptor binding in rat brain synaptic membrane fractions.Brain Res. 10081–97.Google Scholar
- Gottesfeld, Z., Kelly, J. S., and Renaud, L. P. (1972). Thein vivo neuropharmacology of amino-oxyacetic acid in the cerebral cortex of the cat.Brain Res. 42319–335.Google Scholar
- Hablitz, J. J., and Langmoen, I. A. (1982). Excitation of hippocampal pyramidal cells by glutamate in the guinea-pig and rat.J. Physiol. (Lond.)325317–331.Google Scholar
- Halliwell, J. V., and Adams, P. R. (1982). Voltage clamp analysis of muscarinic excitation in hippocampal neurons.Brain Res. 25071–92.Google Scholar
- Homma, S., and Rovainen, C. M. (1978). Conductance increases produced by glycine andγ-aminobutyric acid in lamprey interneurones.J. Physiol. (Lond.)279231–252.Google Scholar
- Horowitz, I. S., and Orkand, R. K. (1980). GABA inactivation at the crayfish neuromuscular junction.J. Neurobiol. 11447–458.Google Scholar
- Iversen, L. L., and Bloom, F. E. (1972). Studies on the uptake of3H-GABA and [3H]glycine in slices and homogenates of rat brain and spinal cord by electron microscopic autoradiography.Brain Res. 41131–143.Google Scholar
- Iversen, L. L., and Neal, M. J. (1968). The uptake of [3H]GABA by slices of rat cerebral cortex.J. Neurochem. 151141–1149.Google Scholar
- Johnston, D., Hablitz, J. J., and Wilson, W. A. (1980). Voltage clamp discloses slow inward current in hippocampal burst-firing neurones.Nature (Lond.)286391–393.Google Scholar
- Katz, B., and Miledi, R. (1973). The binding of acetylcholine to receptors and its removal from the synaptic cleft.J. Physiol. (Lond.)231549–574.Google Scholar
- Krause, D. N., Ikeda, K., and Roberts, E. (1981). Dose-conductance relationships for GABA agonists and the effect of uptake inhibitors in crayfish stretch receptor neurons.Brain Res. 225319–332.Google Scholar
- Krogsgaard-Larsen, P., and Johnston, G. A. R. (1975). Inhibition of GABA uptake in brain slices by nipecotic acid, various isoxazoles and related compounds.J. Neurochem. 25797–802.Google Scholar
- Lebeda, F. J., and Hablitz, J. J. (1982). Apparent sensitization of GABA-induced responses in hippocampal neurons.Soc. Neurosci. Abstr. 8796, 1982.Google Scholar
- Lebeda, F. J., Hablitz, J. J., and Johnston, D. (1982). Antagonism of GABA-mediated responses byd-tubocurarine in hippocampal neurons.J. Neurophysiol. 48622–632.Google Scholar
- Lester, B. R., Miller, A. L., and Peck, E. J. (1981). Differential solubilization ofγ-aminobutyric acid receptive sites from membranes of mammalian brain.J. Neurochem. 36154–164.Google Scholar
- Lodge, D., Johnston, G. A. R., Curtis, D. R., and Brand, S. J. (1977). Effects of the areca nut constituents arecaidine and guvacine on the action of GABA in the cat central nervous system.Brain Res. 136513–522.Google Scholar
- Logan, W. J., and Snyder, S. H. (1971). Unique high affinity uptake systems for glycine, glutamic and aspartic acids in central nervous tissue of the rat.Nature (Lond.)234297–299.Google Scholar
- Nistri, A., and Constanti, A. (1979). Pharmacological characterization of different types of GABA and glutamate receptors in vertebrates and invertebrates.Prog. Neurobiol. 13117–235.Google Scholar
- Olsen, R. W., Ticku, M. K., Van Ness, P. C., and Greenlee, D. (1978). Effects of drugs onγ-aminobutyric acid receptors, uptake, release and synthesis in vitro.Brain Res. 139277–294.Google Scholar
- Provencher, S. W. (1976). A Fourier method for the analysis of exponential decay curves.Biophys. J. 16 27–41.Google Scholar
- Purves, R. D. (1977). The release of drugs from iontophoretic pipettes.J. Theor. Biol. 66789–798.Google Scholar
- Storm-Mathisen, J., and Fonnum, F. (1971). Quantitative histochemistry of glutamate decarboxylase in the rat hippocampal region.J. Neurochem. 181105–1111.Google Scholar
- Van Gelder, N. M. (1965). A comparison ofγ-aminobutyric acid metabolism in rabbit and mouse nervous tissue.J. Neurochem. 12239–244.Google Scholar
- Waud, D. R. (1969). Appendix: A quantitative model for the effect of a saturable uptake on the slope of the dose-response curve.J. Pharmacol. Exp. Ther. 167140–142.Google Scholar
- Weeg, G. P., and Reed, G. B. (1966).Introduction to Numerical Analysis, Blaisdell, Waltham, Mass.Google Scholar