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GABA uptake regulates cortical excitability via cell type–specific tonic inhibition

Nature Neuroscience volume 6, pages 484–490 (2003)Cite this article

Abstract

GABAA receptors can mediate both 'phasic' synaptic inhibition and a persistent 'tonic' form of signaling. We show that, in the presence of intact GABA uptake, guinea pig hippocampal interneurons, but not pyramidal cells, express a tonic GABAA receptor–mediated conductance. This conductance was pharmacologically distinct from spontaneous inhibitory postsynaptic currents (IPSCs). Inhibiting GABA uptake resulted in the expression of a comparable GABAA receptor–mediated tonic conductance in pyramidal cells. Reducing the tonic conductance in interneurons enhanced their excitability and the inhibitory drive to pyramidal cells. These results point to a role for cell type–dependent tonic inhibition in regulating cortical excitability.

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Figure 1: Interneurons but not pyramidal cells express a picrotoxin- and zolpidem-sensitive tonic GABAA receptor–mediated conductance.
Figure 2: Synaptic GABAA receptor-mediated currents, but not the tonic GABAA receptor-mediated current in interneurons, are sensitive to 0.5 μM SR95531 and 50 μM L-AP4.
Figure 3: Blocking GABA uptake results in the expression of a pharmacologically identical tonic current in pyramidal cells.
Figure 4: The GABAA receptor–mediated tonic current and its differential expression in interneurons and pyramidal cells persist at higher temperatures.
Figure 5: Inhibition of the interneuron-specific tonic current increases the excitability of interneurons and the frequency of sIPSCs in pyramidal cells.

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References

  1. Whittington, M.A., Traub, R.D. & Jefferys, J.G. Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature 373, 612–615 (1995).

    Article  CAS  Google Scholar 

  2. Isaacson, J.S., Solis, J.M. & Nicoll, R.A. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 10, 165–175 (1993).

    Article  CAS  Google Scholar 

  3. Rossi, D.J. & Hamann, M. Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry. Neuron 20, 783–795 (1998).

    Article  CAS  Google Scholar 

  4. Birnir, B., Everitt, A.B., Lim, M.S. & Gage, P.W. Spontaneously opening GABA(A) channels in CA1 pyramidal neurones of rat hippocampus. J. Membr. Biol. 174, 21–29 (2000).

    Article  CAS  Google Scholar 

  5. Brickley, S.G., Cull-Candy, S.G. & Farrant, M. Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J. Physiol. (Lond.) 497, 753–759 (1996).

    Article  CAS  Google Scholar 

  6. Wall, M.J. & Usowicz, M.M. Development of action potential-dependent and independent spontaneous GABAA receptor–mediated currents in granule cells of postnatal rat cerebellum. Eur. J. Neurosci. 9, 533–548 (1997).

    Article  CAS  Google Scholar 

  7. Overstreet, L.S. & Westbrook, G.L. Paradoxical reduction of synaptic inhibition by vigabatrin. J. Neurophysiol. 86, 596–603 (2001).

    Article  CAS  Google Scholar 

  8. Nusser, Z. & Mody, I. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J. Neurophysiol. 87, 2624–2628 (2002).

    Article  CAS  Google Scholar 

  9. Stell, B.M. & Mody, I. Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons. J. Neurosci. 22, RC223 (2002).

    Article  Google Scholar 

  10. Bai, D. et al. Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons. Mol. Pharmacol. 59, 814–824 (2001).

    Article  CAS  Google Scholar 

  11. Wisden, W. et al. Ectopic expression of the GABA(A) receptor alpha6 subunit in hippocampal pyramidal neurons produces extrasynaptic receptors and an increased tonic inhibition. Neuropharmacology 43, 530 (2002).

    Article  CAS  Google Scholar 

  12. Draguhn, A. & Heinemann, U. Different mechanisms regulate IPSC kinetics in early postnatal and juvenile hippocampal granule cells. J. Neurophysiol. 76, 3983–3993 (1996).

    Article  CAS  Google Scholar 

  13. Yan, X.X., Cariaga, W.A. & Ribak, C.E. Immunoreactivity for GABA plasma membrane transporter, GAT-1, in the developing rat cerebral cortex: transient presence in the somata of neocortical and hippocampal neurons. Brain Res. Dev. Brain Res. 99, 1–19 (1997).

    Article  CAS  Google Scholar 

  14. Demarque, M. et al. Paracrine intercellular communication by a Ca2+- and SNARE-independent release of GABA and glutamate prior to synapse formation. Neuron 36, 1051–1061 (2002).

    Article  CAS  Google Scholar 

  15. Nusser, Z., Sieghart, W. & Somogyi, P. Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 18, 1693–1703 (1998).

    Article  CAS  Google Scholar 

  16. Brickley, S.G., Revilla, V., Cull-Candy, S.G., Wisden, W. & Farrant, M. Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature 409, 88–92 (2001).

    Article  CAS  Google Scholar 

  17. Saxena, N.C. & Macdonald, R.L. Assembly of GABAA receptor subunits: role of the delta subunit. J. Neurosci. 14, 7077–7086 (1994).

    Article  CAS  Google Scholar 

  18. Hamann, M., Rossi, D.J. & Attwell, D. Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex. Neuron 33, 625–633 (2002).

    Article  CAS  Google Scholar 

  19. Curmi, J.P., Premkumar, L.S., Birnir, B. & Gage, P.W. The influence of membrane potential on chloride channels activated by GABA in rat cultured hippocampal neurons. J. Membr. Biol. 136, 273–280 (1993).

    Article  CAS  Google Scholar 

  20. Semyanov, A. & Kullmann, D.M. Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Neuron 25, 663–672 (2000).

    Article  CAS  Google Scholar 

  21. Gulyas, A.I., Megias, M., Emri, Z. & Freund, T.F. Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus. J. Neurosci. 19, 10082–10097 (1999).

    Article  CAS  Google Scholar 

  22. Megias, M., Emri, Z., Freund, T.F. & Gulyas, A.I. Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells. Neuroscience 102, 527–540 (2001).

    Article  CAS  Google Scholar 

  23. Woodson, W., Nitecka, L. & Ben-Ari, Y. Organization of the GABAergic system in the rat hippocampal formation: a quantitative immunocytochemical study. J. Comp. Neurol. 280, 254–271 (1989).

    Article  CAS  Google Scholar 

  24. Collingridge, G.L., Gage, P.W. & Robertson, B. Inhibitory post-synaptic currents in rat hippocampal CA1 neurones. J. Physiol. 356, 551–564 (1984).

    Article  CAS  Google Scholar 

  25. De Koninck, Y. & Mody, I. Noise analysis of miniature IPSCs in adult rat brain slices: properties and modulation of synaptic GABAA receptor channels. J. Neurophysiol. 71, 1318–1335 (1994).

    Article  CAS  Google Scholar 

  26. Vizi, E.S. & Sperlagh, B. Separation of carrier mediated and vesicular release of GABA from rat brain slices. Neurochem. Int. 34, 407–413 (1999).

    Article  CAS  Google Scholar 

  27. Newland, C.F. & Cull-Candy, S.G. On the mechanism of action of picrotoxin on GABA receptor channels in dissociated sympathetic neurons of the rat. J. Physiol. 447, 191–213 (1992).

    Article  CAS  Google Scholar 

  28. Dillon, G.H., Im, W.B., Carter, D.B. & McKinley, D.D. Enhancement by GABA of the association rate of picrotoxin and tert- butylbicyclophosphorothionate to the rat cloned alpha 1 beta 2 gamma 2 GABAA receptor subtype. Br. J. Pharmacol. 115, 539–545 (1995).

    Article  CAS  Google Scholar 

  29. Borden, L.A. GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem. Int. 29, 335–356 (1996).

    Article  CAS  Google Scholar 

  30. Lerma, J., Herranz, A.S., Herreras, O., Abraira, V. & Martin del Rio, R. In vivo determination of extracellular concentration of amino acids in the rat hippocampus. A method based on brain dialysis and computerized analysis. Brain Res. 384, 145–155 (1986).

    Article  CAS  Google Scholar 

  31. Peng, Z. et al. GABA(A) receptor changes in delta subunit-deficient mice: altered expression of alpha4 and gamma2 subunits in the forebrain. J. Comp. Neurol. 446, 179–197 (2002).

    Article  CAS  Google Scholar 

  32. Wingrove, P.B., Thompson, S.A., Wafford, K.A. & Whiting, P.J. Key amino acids in the gamma subunit of the gamma-aminobutyric acidA receptor that determine ligand binding and modulation at the benzodiazepine site. Mol. Pharmacol. 52, 874–881 (1997).

    Article  CAS  Google Scholar 

  33. Eghbali, M., Curmi, J.P., Birnir, B. & Gage, P.W. Hippocampal GABA(A) channel conductance increased by diazepam. Nature 388, 71–75 (1997).

    Article  CAS  Google Scholar 

  34. Yeung, J.Y. et al. Tonically activated GABAA receptors in hippocampal neurons are high-affinity, low-conductance sensors for extracellular GABA. Mol. Pharmacol. 63, 2–8 (2003).

    Article  CAS  Google Scholar 

  35. Hamann, M., Desarmenien, M., Desaulles, E., Bader, M.F. & Feltz, P. Quantitative evaluation of the properties of a pyridazinyl GABA derivative (SR 95531) as a GABAA competitive antagonist. An electrophysiological approach. Brain. Res. 442, 287–296 (1988).

    Article  CAS  Google Scholar 

  36. Engel, D. et al. Laminar difference in GABA uptake and GAT-1 expression in rat CA1. J. Physiol. 512, 643–649 (1998).

    Article  CAS  Google Scholar 

  37. Radian, R., Ottersen, O.P., Storm-Mathisen, J., Castel, M. & Kanner, B.I. Immunocytochemical localization of the GABA transporter in rat brain. J. Neurosci. 10, 1319–1330 (1990).

    Article  CAS  Google Scholar 

  38. Ribak, C.E., Tong, W.M. & Brecha, N.C. GABA plasma membrane transporters, GAT-1 and GAT-3, display different distributions in the rat hippocampus. J. Comp. Neurol. 367, 595–606 (1996).

    Article  CAS  Google Scholar 

  39. Chiu, C.S. et al. Number, density, and surface/cytoplasmic distribution of GABA transporters at presynaptic structures of knock-in mice carrying GABA transporter subtype 1-green fluorescent protein fusions. J. Neurosci. 22, 10251–10266 (2002).

    Article  CAS  Google Scholar 

  40. Liu, Q.Y., Schaffner, A.E., Chang, Y.H., Maric, D. & Barker, J.L. Persistent activation of GABA(A) receptor/Cl(−) channels by astrocyte- derived GABA in cultured embryonic rat hippocampal neurons. J. Neurophysiol. 84, 1392–1403 (2000).

    Article  CAS  Google Scholar 

  41. Frahm, C. & Draguhn, A. GAD and GABA transporter (GAT-1) mRNA expression in the developing rat hippocampus. Brain Res. Dev. Brain Res. 132, 1–13 (2001).

    Article  CAS  Google Scholar 

  42. Celio, M.R. Perineuronal nets of extracellular matrix around parvalbumin-containing neurons of the hippocampus. Hippocampus 3, 55–60 (1993).

    PubMed  Google Scholar 

  43. Brooks-Kayal, A.R., Shumate, M.D., Jin, H., Rikhter, T.Y. & Coulter, D.A. Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat. Med. 4, 1166–1172 (1998).

    Article  CAS  Google Scholar 

  44. During, M.J., Ryder, K.M. & Spencer, D.D. Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature 376, 174–177 (1995).

    Article  CAS  Google Scholar 

  45. Hausser, M. & Clark, B.A. Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration. Neuron 19, 665–678 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to members of the laboratory for comments. This work was supported by the Medical Research Council (D.M.K. and A.S.) and the Wellcome Trust (M.C.W.).

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  1. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK

    Alexey Semyanov, Matthew C. Walker & Dimitri M. Kullmann

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Correspondence to Dimitri M. Kullmann.

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Semyanov, A., Walker, M. & Kullmann, D. GABA uptake regulates cortical excitability via cell type–specific tonic inhibition. Nat Neurosci 6, 484–490 (2003). https://doi.org/10.1038/nn1043

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