Skip to main content
SpringerLink
Log in

In Vivo Function of GABAA Receptor Subtypes Unraveled With Mutant Mice

  • Chapter
Molecular Neuropharmacology

  • 205 Accesses

Abstract

GABAA receptors mediate most of the fast inhibitory transmission in the brain, and therefore modulate almost every aspect of brain function. In addition, they represent a major site of action for clinically important drugs, including benzodiazepines, barbiturates, neurosteroids, some general anesthetics, as well as drugs of abuse, such as ethanol (1–4). All these drugs act by increasing GABA function by allosteric interaction or by direct action on the channel. Clinically, the significance of GABAA receptor function is underscored by the multiple neurological and psychiatric diseases for which an alteration in the GABAergic system has been postulated (5), including epilepsy (6–8),anxiety disorders (9), ethanol dependence (10), Huntington’s disease (11), Angelman syndrome (12),and schizophrenia (13–15).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Sieghart, W. (1995) Structure and pharmacology of γ-aminobutyric acid, receptor subtypes. Pharmacol. Rev. 47, 181–234.

    PubMed  CAS  Google Scholar 

  2. Dilger, J. P. (2002) The effects of general anaesthetics on ligand-gated ion channels. Br. J. Anaest. 89, 41–51.

    Article  CAS  Google Scholar 

  3. Mohler, H., Fritschy, J. M., and Rudolph, U. (2002) A new benzodiazepine pharmacology. J. Pharm. Exp. Ther. 300, 2–8.

    Article  CAS  Google Scholar 

  4. Grobin, A. C., Matthews, D. B., Devaud, L. L., and Morrow, A. L. (1998) The role of GABA, receptors in the acute and chronic effects of ethanol. Psychopharmacology 139, 2–19.

    Article  PubMed  CAS  Google Scholar 

  5. Mohler, H. (2000) Functions of GABA,-receptors: pharmacology and pathophysiology, in Pharmacology of GABA and Glycine Neurotransmission (Mohler, H., ed.), Springer-Verlag, Berlin, pp. 101–116.

    Google Scholar 

  6. Duncan, J. S. (1999) Positron emission tomography receptor studies in epilepsy. Rev. Neurol. 155, 482–488.

    PubMed  CAS  Google Scholar 

  7. Olsen, R. W., DeLorey, T. M., Gordey, M., and Kang, M. H. (1999) GABA receptor function and epilepsy. Adv. Neurol. 79, 499–510.

    PubMed  CAS  Google Scholar 

  8. Coulter, D. A. (2001) Epilepsy-associated plasticity in y-aminobutyric acid-, receptor expression, function, and inhibitory synaptic properties. Int. Rev. Neurobiol. 45, 237–252.

    Article  PubMed  CAS  Google Scholar 

  9. Malizia, A. L. (1999) What do brain imaging studies tell us about anxiety disorders ? J. Psychopharmacol. 13, 372–378.

    Article  PubMed  CAS  Google Scholar 

  10. Morrow, A. L., VanDoren, M. J., Penland, S. N., and Matthews, D. B. (2001) The role of GABAergic neuroactive steroids in ethanol action, tolerance and dependence. Brain Res. Rev. 37, 98–109.

    Article  PubMed  CAS  Google Scholar 

  11. Kunig, G., Leenders, K. L., Sanchez-Pernaute, R., Antonini, A., Vontobel, P., Verhagen, A., and Gunther, I. (2000) Benzodiazepine receptor binding in Huntington’s disease: [’ 1C]flumazenil uptake measured using positron. Ann. Neurol. 47, 644–648.

    Article  PubMed  CAS  Google Scholar 

  12. DeLorey, T. M., Handforth, A., Anagnostaras, S. G., Homanics, G. E., Minassian, B. A., Asatourian, A., et al. (1998) Mice lacking the 133 subunit of the GABA, receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J. Neurosci. 18, 8505–8514.

    PubMed  CAS  Google Scholar 

  13. Nutt, D. J. and Malizia, A. L. (2001) New insights into the role of the GABA,-benzodiazepine receptor in psychiatric disorder. Br. J. Psychiat. 179, 390–396.

    Article  CAS  Google Scholar 

  14. Blum, B. P. and Mann, J. J. (2002) The GABAergic system in schizophrenia. Int. J. Neuropsychopharmacol. 5, 159–179.

    Article  PubMed  CAS  Google Scholar 

  15. Lewis, D. A. (2000) GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. Brain Res. Rev. 31, 270–276.

    Article  PubMed  CAS  Google Scholar 

  16. Unwin, N. (1993) Neurotransmitter action: opening of a ligand-gated channel. Neuron 10 Suppl., 31–41.

    Google Scholar 

  17. Barnard, E. A. (2001) The molecular architecture of GABA, receptors, in Pharmacology of GABA and Glycine Neurotransmission, vol. 150 ( Mohler, H., ed.), Springer-Verlag, Berlin, pp. 79–100.

    Chapter  Google Scholar 

  18. Barnard, E. A., Skolnick, P., Olsen, R. W., et aI. (1998) International Union of Pharmacology. XV. Subtypes of y-aminobutyric acid, receptors: classification on the basis of subunit structure and function. Pharmacol. Rev. 50, 291–313.

    PubMed  CAS  Google Scholar 

  19. Whiting, P. J. (1999) The GABA, receptor gene family: new targets for therapeutic intervention. Neurochem. Int. 34, 387–390.

    Article  PubMed  CAS  Google Scholar 

  20. Mohler, H., Fritschy, J. M., Luscher, B., Rudolph, U., Benson, J., and Benke, D. (1996) The GABA,-receptors: from subunits to diverse functions, in Ion Channels vol. 4 ( Narahashi, T., ed.), Plenum Press, New York, pp. 89–113.

    Google Scholar 

  21. Knight, A. R., Stephenson, E. A., Tallman, J. F., and Ramabandran, T. V. (2000) Monospecific antibodies as probes for the stoichiometry of recombinant GABAA receptors. Recept. Channels 7, 213–226.

    PubMed  CAS  Google Scholar 

  22. Baumann, S. W., Baur, R., and Sigel, E. (2001) Subunit arrangement of y-aminobutyric acid type A receptors..1. Biol. Chem. 276, 36275–36280.

    Google Scholar 

  23. Klausberger, T., Sarto, I., Ehya, N., et al. (2001) Alternate use of distinct intersubunit contacts controls GABAA receptor assembly and stoichiometry. J. Neurosci. 21, 9124–9133.

    PubMed  CAS  Google Scholar 

  24. Farrar, S. J., Whiting, P. J., Bonnert, T. P., and McKernan, R. M. (1999) Stoichiometry of a ligand-gated ion channel determined by fluorescence energy transfer. J. Biol. Chem. 274, 10100–10104.

    Article  PubMed  CAS  Google Scholar 

  25. Bormann, J. (2000) The “ABC” of GABA receptors. Trends Pharmacol. Sci. 21, 16–19.

    Article  PubMed  CAS  Google Scholar 

  26. Benson, J. A., Löw, K., Keist, R., Mohler, H., and Rudolph, U. (1998) Pharmacology of recombinant y-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated a-subunits. FEBS Lett. 431, 400–404.

    Google Scholar 

  27. Wingrove, P. B., Safo, R, Wheat, L., Thompson, S. A., Wafford, K. A., and Whiting, P. J. (2002) Mechanism of a-subunit selectivity of benzodiazepine pharmacology at yaminobutyric acid type A receptors. Eur. J. Pharmacol. 437, 31–39.

    Article  PubMed  CAS  Google Scholar 

  28. Verdoorn, T. A., Draguhn, A., Ymer, S., Seeburg, P. H., and Sakmann, B. (1990) Functional properties of recombinant rat GABAA receptors depend upon subunit composition. Neuron 4, 919–928.

    Article  PubMed  CAS  Google Scholar 

  29. Hutcheon, B., Morley, P., and Poulter, M. 0. (2000) Developmental change in GABAA receptor desensitization kinetics and its role in synapse function in rat cortical neurons..1. Physiol. 522, 3–17.

    Article  CAS  Google Scholar 

  30. Devor, A., Fritschy, J. M., and Yarom, Y. (2001) Spatial distribution and subunit composition of GABAA receptors in the inferior olivary nucleus. J. Neurophysiol. 85, 1686–1696.

    PubMed  CAS  Google Scholar 

  31. Burgard, E. C., Tietz, E. I., Neelands, T. R., and Macdonald, R. L. (1996) Properties of recombinant y-aminobutyric acidA receptor isoforms containing the a5 subunit subtype. Mol. Pharmacol. 50, 119–127.

    PubMed  CAS  Google Scholar 

  32. Fisher, J. L. and Macdonald, R. L. (1997) Single channel properties of recombinant GABAA receptors containing y2 or S subtypes expressed with ai and 133 subtypes in mouse L929 cells. J. Physiol. 505, 283–297.

    Article  PubMed  CAS  Google Scholar 

  33. Adkins, C. E., Pillai, G. V., Kerby, J., et al. (2001) a4f33S GABAA receptors characterized by fluorescence resonance energy transfer-derived measurements of membrane potential. J. Biol. Chem. 276, 38934–38939.

    Google Scholar 

  34. Schwarzer, C., Berresheim, U., Pirker, S., Wieselthaler, A., Fuchs, K., Sieghart, W., and Sperk, G. (2001) Distribution of the major y-aminobutyric acidA receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat. J. Comp. Neurol. 433, 526–549.

    Article  PubMed  CAS  Google Scholar 

  35. Waldvogel, H. J., Fritschy, J. M., Mohler, H., and Faull, R. L. M. (1998) GABAA receptors in the primate basal ganglia: an autoradiographic and a light and electron microscopic immunohistochemical study of the al and 02,3 subunits in the baboon brain. J. Comp. Neurol. 397, 297–325.

    Article  PubMed  CAS  Google Scholar 

  36. Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W., and Sperk, G. (2000) GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101, 815–850.

    Article  PubMed  CAS  Google Scholar 

  37. Fritschy, J. M. and Mohler, H. (1995) GABAA receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359, 154–194.

    Article  PubMed  CAS  Google Scholar 

  38. Hornung, J. R. and Fritschy, J. M. (1996) Developmental profile of GABAA-receptors in the marmoset monkey: expression of distinct subtypes in pre-and postnatal brain. J. Comp. Neurol. 367, 413–430.

    Article  PubMed  CAS  Google Scholar 

  39. Nusser, Z., Sieghart, W., Benke, D., Fritschy, J. M., and Somogyi, P. (1996) Differential synaptic localization of two major y-aminobutyric acid type A receptor a subunits on hippocampal pyramidal neurons. Proc. Natl. Acad. Sci. USA 93, 11939–11944.

    Article  PubMed  CAS  Google Scholar 

  40. Fritschy, J. M., Weinmann, O., Wenzel, A., and Benke, D. (1998) Synapse-specific localization of NMDA- and GABAA-receptor subunits revealed by antigen-retrieval immunohistochemistry. J. Comp. Neurol. 390, 194–210.

    Article  PubMed  CAS  Google Scholar 

  41. Brünig, I., Scotti, E., Sidler, C., and Fritschy, J. M. (2002) Intact sorting, targeting, and clustering of y-aminobutyric acid A receptor subtypes in hippocampal neurons in vitro. J. Comp. Neurol. 443, 43–45.

    Article  PubMed  CAS  Google Scholar 

  42. Crestani, F., Keist, R., Fritschy, J. M., et al. (2002) Trace fear conditioning involves hippocampal a5 GABAA receptors. Proc. Natl. Acad. Sci. USA 99, 8980–8985.

    Article  CAS  Google Scholar 

  43. Uusi-Oukari, M., Heikkilä, J., Sinkkonen, S. T., et al. (2000) Long-range interactions in neuronal gene expression: evidence from gene targeting in the GABAA receptor 32–a6–a1Y2 subunit gene cluster. Mol. Cell. Neurosci. 16, 34–41.

    Article  PubMed  CAS  Google Scholar 

  44. Russek, S. J. (1999) Evolution of GABAA receptor diversity in the human genome. Gene 227, 213–222.

    Article  PubMed  CAS  Google Scholar 

  45. Bailey, M. E. S., Matthews, D. A., Riley, B. P., Albrecht, B. E., Kostrzewa, M., Hicks, A. A., et al. (1999) Genomic mapping and evolution of human GABAA receptor subunit gene clusters. Mammal. Gen. 10, 839–843.

    Article  CAS  Google Scholar 

  46. Connolly, C. N., Uren, J. M., Thomas, P., Gorrie, G. H., Gibson, A., Smart, T. G., and Moss, S. J. (1999) Subcellular localization and endocytosis of homomeric 12 subunit splice variants of y-aminobutyric acid type A receptors. Mol. Cell. Neurosci. 13, 259–271.

    Article  PubMed  CAS  Google Scholar 

  47. Connolly, C. N., Krishek, B. J., McDonald, B. J., Smart, T. G., and Moss, S. J. (1996) Assembly and cell surface expression of heteromeric and homomeric y-aminobutyric acid type A receptors. J. Biol. Chem. 271, 89–96.

    Article  PubMed  CAS  Google Scholar 

  48. Mihic, S. J. and Harris, R. A. (1996) Inhibition of rhol receptor GABAergic currents by alcohols and volatile anesthetics. J. Pharmacol. Exp. Ther. 277, 411–416.

    PubMed  CAS  Google Scholar 

  49. Amin, J. and Weiss, D. S. (1994) Homomeric p 1 GABA channels: activation properties and domains. Recept. Channels. 2, 227–236.

    PubMed  CAS  Google Scholar 

  50. Pritchett, D. B., Sontheimer, H., Shivers, B. D., Ymer, S., Kettenmann, H., Schofield, P. R., and Seeburg, P. H. (1989) Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature 338, 582–585.

    Article  PubMed  CAS  Google Scholar 

  51. Lorez, M., Benke, D., Luscher, B., Mohler, H., and Benson, J. A. (2000) Single-channel properties of neuronal GABAA receptors from mice lacking the y2 subunit. J. Physiol. 527, 11–31.

    Article  PubMed  CAS  Google Scholar 

  52. Gunther, U., Benson, J., Benke, D., et al. (1995) Benzodiazepine-insensitive mice generated by targeted disruption of the y2–subunit gene of y-aminobutyric acid type A receptors. Proc. Natl. Acad. Sci. USA 92, 7749–7753.

    Article  PubMed  CAS  Google Scholar 

  53. Collinson, N., Kuenzi, F. M., Jarolimek, W., et al. (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the a5 subunit of the GABAA receptor. J. Neurosci. 22, 5572–5580.

    PubMed  CAS  Google Scholar 

  54. Sur, C., Wafford, K. A., Reynolds, D. S., et al. (2001) Loss of the major GABAA receptor subtype in the brain is not lethal in mice. J. Neurosci. 21, 3409–3418.

    PubMed  CAS  Google Scholar 

  55. Kralic, J. E., Korpi, E. R., O’Buckley, T. K., Homanics, G. E., and Morrow, A. (2002) Molecular and pharmacological characterization of GABAA receptor ai subunit knockout mice. J. Pharmacol. Exp. Ther. 302, 1037–1045.

    CAS  Google Scholar 

  56. Krasowski, M. D., Rick, C. E., Harrison, N. L., Firestone, L., and Homanics, G. E. (1998) A deficit of functional GABAA receptors in neurons of 133 subunit knockout mice. Neurosci. Lett. 240, 81–84.

    Article  PubMed  CAS  Google Scholar 

  57. Homanics, G. E., Delorey, T. M., Firestone, L. L., et al. (1997) Mice devoid of y-aminobutyrate type A receptor (33 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Natl. Acad. Sci. USA 94, 4143–4148.

    Article  PubMed  CAS  Google Scholar 

  58. Fritschy, J. M., Benke, D., Johnson, D. K., Mohler, H., and Rudolph, U. (1997) GABAAreceptor a-subunit is an essential prerequisite for receptor formation in vivo. Neuroscience 81, 1043–1053.

    Article  PubMed  CAS  Google Scholar 

  59. Nusser, Z., Ahmad, Z., Tretter, V., Fuchs, K., Wisden, W., Seighart, W., and Somogyi, P. (1999) Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the a6 subunit gene. Eur. J. Neurosci. 11, 1685–1697.

    Article  PubMed  CAS  Google Scholar 

  60. Kralic, J. E., O’Buckley, T. K., Khisti, R. T., Hodge, C. J., Homanics, G. E., and Morrow, A. L. (2002) GABAA receptor al subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 43, 685–694.

    Article  PubMed  CAS  Google Scholar 

  61. Fritschy, J. M., Johnson, D. K., Mohler, H., and Rudolph, U. (1998) Independent assembly and subcellular targeting of GABAA receptor subtypes demonstrated in mouse hippocampal and olfactory neurons in vivo. Neurosci. Lett. 249, 99–102.

    Article  PubMed  CAS  Google Scholar 

  62. Jones, A., Korpi, E. R., McKernan, R. M., et al. (1997) Ligand-gated ion channel subunit partnerships: GABAA receptor a6 subunit gene inactivation inhibits delta subunit expression. J. Neurosci. 17, 1350–1362.

    PubMed  CAS  Google Scholar 

  63. Peng, Z., Hauer, B., Mihalek, R. M., Homanics, G. E., Sieghart, W., Olsen, R. W., and Houser, C. R. (2002) GABAA receptor changes in 8 subunit-deficient mice: altered expression of a4 and y2 subunits in the forebrain. J. Comp. Neurol. 446, 179–197.

    Article  PubMed  CAS  Google Scholar 

  64. Korpi, E. R., Mihalek, R. M., Sinkkonen, S. T., et al. (2002) Altered receptor subtypes in the forebrain of GABAA receptor 8 subunit-deficient mice: recruitment of y2 subunits. Neuroscience 109, 733–743.

    Article  PubMed  CAS  Google Scholar 

  65. Tretter, V., Hauer, B., Nusser, Z., et al. (2001) Targeted disruption of the GABAA receptor 8 subunit gene leads to an up-regulation of y2 subunit-containing receptors in cerebellar granule cells. J. Biol. Chem. 276, 10532–10538.

    Article  PubMed  CAS  Google Scholar 

  66. Wohlfarth, K. M., Bianchi, M. T., and Macdonald, R. L. (2002) Enhanced neurosteroid potentiation of ternary GABAA receptors containing the 8 subunit. J. Neurosci. 22, 1541–1549.

    PubMed  CAS  Google Scholar 

  67. Lin, Y. F., Angelotti, T. P., Dudek, E. M., Browning, M. D., and Macdonald, R. L. (1996) Enhancement of recombinant a131y2L y-aminobutyric acid, receptor whole-cell currents by protein kinase C is mediated through phosphorylation of both 131 and 12L subunits. Mol. Pharmacol. 50, 185–195.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  69. Benke, D., Honer, M., Michel, C., and Mohler, H. (1996) GABAA receptor subtypes differentiated by their y-subunit variants: prevalence, pharmacology and subunit architercture. Neuropharmacology 35, 1413–1422.

    Article  PubMed  CAS  Google Scholar 

  70. Essrich, C., Lorez, M., Benson, J. A., Fritschy, J. M., and Luscher, B. (1998) Postsynaptic clustering of major GABAA receptor subtypes requires the y2 subunit and gephyrin. Nature Neurosci. 1, 563–571.

    Article  PubMed  CAS  Google Scholar 

  71. Kneussel, M., Brandstatter, J. H., Laube, B., Stahl, S., Muller, U., and Betz, H. (1999) Loss of postsynaptic GABAA receptor clustering in gephyrin-deficient mice. J. Neurosci. 19, 9289–9297.

    PubMed  CAS  Google Scholar 

  72. Briinig, I., Suter, A., Knuesel, I., Luscher, B., and Fritschy, J. M. (2002) GABAergic presynaptic terminals are required for postsynaptic clustering of dystrophin, but not of GABAA receptors and gephyrin. J. Neurosci. 22, 4805–4813.

    Google Scholar 

  73. Baer, K., Essrich, C., Benson, J. A., Benke, D., Bluethmann, H., Fritschy, J. M., and Luscher, B. (1999) Postsynaptic clustering of y-aminobutyric acid type A receptors by the 73 subunit in vivo. Proc. Natl. Acad. Sci. USA 96, 12860–12865.

    Article  PubMed  CAS  Google Scholar 

  74. Mihalek, R. M., Banerjee, P. K., Korpi, E. R., and Quinlan, J. J. (1999) Attenuated sensitivity to neuroactive steroids in y-aminobutyrate type A receptor 8 subunit knockout mice. Proc. Natl. Acad. Sci. USA 96, 12905–12910.

    Article  PubMed  CAS  Google Scholar 

  75. Mihalek, R. M., Bowers, B. J., Wehner, J. M., Kralic, J. E., VanDoren, M. J., Morrow, A. L., and Homanics, G. E. (2001) GABAA receptor 6 subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol. Clin. Exp. Res. 25, 1708–1718.

    PubMed  CAS  Google Scholar 

  76. Homanics, G. E., Ferguson, C., Quinlan, J. J., et al. (1997) Gene knockout of the a6 subunit of the y-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol. Pharmacol. 51, 588–596.

    PubMed  CAS  Google Scholar 

  77. Wafford, K. A. and Whiting, P. J. (1992) Ethanol potentiation of GABAA receptors requires phosphorylation of the alternatively spliced variant of the y2 subunit. FEBS Lett. 313, 113–117.

    Article  PubMed  CAS  Google Scholar 

  78. Sigel, E., Baur, R., and Malherbe, P. (1993) Recombinant GABAA receptor function and ethanol. FEBS Lett. 324, 140–142.

    Article  PubMed  CAS  Google Scholar 

  79. Mihic, S. J., Whiting, P. J., and Harris, R. A. (1994) Anaesthetic concentrations of alcohols potentiate GABAA receptor-mediated currents: lack of subunit specificity. Eur. J. Pharmacol. 268, 209–214.

    Article  PubMed  CAS  Google Scholar 

  80. Homanics, G. E., Harrison, N. L., Quinlan, J. J., et al. (1999) Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the 72 subunit of the y-aminobutyrate type A receptor. Neuropharmacology 38, 253–265.

    Article  PubMed  CAS  Google Scholar 

  81. Quinlan, J. J., Firestone, L. L., and Homanics, G. E. (2000) Mice lacking the long splice variant of the y2 subunit of the GABAA receptor are more sensitive to benzodiazepines. Pharmacol. Biochem. Behan 66, 371–374.

    Article  CAS  Google Scholar 

  82. Quinlan, J., Homanics, G., and Firestone, L. (1998) Anesthesia sensitivity in mice that lack the 33 subunit of the y-aminobutyric acid type A receptor. Anesthesiology 88, 775–780.

    Article  PubMed  CAS  Google Scholar 

  83. Wong, S. M., Cheng, G., Homanics, G. E., and Kendig, J. J. (2001) Enflurane actions on spinal cords from mice that lack the 133 subunit of the GABAA receptor. Anesthesiology 95, 154–164.

    Article  PubMed  CAS  Google Scholar 

  84. Ugarte, S. D., Homanics, G. E., Firestone, L. L., and Hammond, D. L. (2000) Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the (33 subunit of the GABAA receptor. Neuroscience 95, 795–806.

    Article  PubMed  CAS  Google Scholar 

  85. Culiat, C. T., Stubbs, L. J., Woychik, R. R, Russell, L. B., Johnson, D. K., and Rinchik, E. M. (1995) Deficiency of the (33 subunit of the type A y-aminobutyric acid receptor causes cleft palate in mice. Nature Genetics 11, 344–346.

    Article  PubMed  CAS  Google Scholar 

  86. Owens, D. F. and Kriegstein, A. R. (2002) Is there more to GABA than synaptic inhibition? Nature Rev. Neurosci. 3, 715–727.

    Article  CAS  Google Scholar 

  87. Ji, F., Kanbara, N., and Obata, K. (1999) GABA and histogenesis in fetal and neonatal mouse brain lacking both the isoforms of glutamic acid decarboxylase. Neurosci. Res. 33, 187–194.

    Article  PubMed  CAS  Google Scholar 

  88. Verhage, M., Maia, A. S., Plomp, J. J., Brussaard, A. B., Heeroma, J. H., Vermeer, H., et al. (2000) Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287, 864–869.

    Article  PubMed  CAS  Google Scholar 

  89. Varoqueaux, F., Sigler, A., Rhee, J. S., Brose, N., Enk, C., Reim, K., and Rosenmund, C. (2002) Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13–mediated vesicle priming. Proc. Natl. Acad. Sci. USA 99, 9037–9042.

    Article  PubMed  CAS  Google Scholar 

  90. Prosser, H. M., Gill, C. H., Hirst, W. D., et al. (2001) Epileptogenesis and enhanced pre-pulse inhibition in GABAB1–deficient Mice. Mol. Cell. Neurosci. 17, 1059–1070.

    Article  PubMed  CAS  Google Scholar 

  91. Schuler, V., Löscher, C., Blanchet, C., et al. (2001) Epilepsy, hyperalgesia, impaired memory, and loss of pre-and postsynaptic GABAB responses in mice lacking GABAB1. Neuron 31, 47–58.

    Article  PubMed  CAS  Google Scholar 

  92. Dellovade, T. L., Davis, A. M., Ferguson, C., Sieghart, W., Homanics, G. E., and Tobet, S. A. (2001) GABA influences the development of the ventromedial nucleus of the hypothalamus. J. Neurobiol. 49, 264–276.

    Article  PubMed  CAS  Google Scholar 

  93. Pannell, C., Simonian, S. X., Gillies, G. E., Luscher, B., and Herbison, A. E. (2002) Hypothalamic somatostatin and growth hormone-releasing hormone mRNA expression depend

    Google Scholar 

  94. upon GABAA receptor expression in the developing mouse. Neuroendocrinology 76, 93–98.

    Google Scholar 

  95. Simonian, S. X., Skynner, M. J., Sieghart, W., Essrich, C., Luscher, B., and Herbison, A. E. (2000) Role of the GABAA receptor y2 subunit in the development of gonadotropin-releasing hormone neurons in vivo. Eur. J. Neurosci. 12, 3488–3496.

    Article  PubMed  CAS  Google Scholar 

  96. Wick, M. J., Radcliffe, R. A., Bowers, B. J., Mascia, M. P., Luscher, B., Harris, R. A., and Wehner, J. M. (2000) Behavioural changes produced by transgenic overexpression of 12L and 12, subunits of the GABAA receptor. Eur. J. Neurosci. 12, 2634–2638.

    Article  PubMed  CAS  Google Scholar 

  97. Baer, K., Essrich, C., Balsiger, S., Wick, M. J., Harris, R. A., Fritschy, J. M., and Luscher, B. (2000) Rescue of y2 subunit-deficient mice by transgenic overexpression of the GABAA receptor y2S or y2, subunit isoforms. Eur. J. Neurosci. 12, 2639–2643.

    Article  PubMed  CAS  Google Scholar 

  98. Fritschy, J. M., Paysan, J., Enna, A., and Mohler, H. (1994) Switch in the expression of rat GABAA-receptor subtypes during postnatal development: an immunohistochemical study. J. Neurosci. 14, 5302–5324.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  100. Tia, S., Wang, J. F., Kotchabhakdi, N., and Vicini, S. (1996) Developmental changes of inhibitory synaptic currents in cerebellar granule neurons: role of GABAA receptor a6 subunit. J. Neurosci. 16, 3630–3640.

    PubMed  CAS  Google Scholar 

  101. Okada, M., Onodera, K., Van Renterghem, C., Sieghart, W., and Takahashi, T. (2000) Functional correlation of GABAA receptor a subunits expression with the properties of IPSCs in the developing thalamus. J. Neurosci. 15, 2202–2208.

    Google Scholar 

  102. Vicini, S., Ferguson, C., Prybylowski, K., Kralic, J., Morrow, A. L., and Homanics, G. E. (2001) GABAA receptor al subunit deletion prevents developmental changes of inhibitory synaptic currents in cerebellar neurons. J. Neurosci. 21, 3009–3016.

    PubMed  CAS  Google Scholar 

  103. Bosman, L. W. J., Rosahl, T. W., and Brussaard, A. B. (2002) Neonatal development of the rat visual cortex: synaptic function of GABAA receptor a subunits. J. Physiol. 545, 169–181.

    Article  PubMed  CAS  Google Scholar 

  104. Miralles, C. P., Li, M., Mehta, A. K., Khan, Z. U., and De Blas., A. L. (1999) Immunocytochemical localization of the [33 subunit of the y-aminobutyric acidA receptor in the rat brain. J. Comp. Neurol. 413, 535–548.

    CAS  Google Scholar 

  105. Nusser, Z., Kay, L. M., Laurent, G., Homanics, G. E., and Mody, I. (2001) Disruption of GABAA receptors on GABAergic interneurons leads to increased oscillatory power in the olfactory bulb network. J. Neurophysiol. 86, 2823–2833.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  107. Huntsman, M. M., Porcello, D. M., Homanics, G. E., DeLorey, T. M., and Huguenard, J. R. (1999) Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science 283, 541–543.

    Article  PubMed  CAS  Google Scholar 

  108. Sohal, V. S., Huntsman, M. M., and Huguenard, J. R. (2000) Reciprocal inhibitory connections regulate the spatiotemporal properties of intrathalamic oscillations. J. Neurosci. 20, 1735–1745.

    PubMed  CAS  Google Scholar 

  109. Spigelman, I., Li, Z., Banerjee, P. K., Mihalek, R. M., Homanics, G. E., and Olsen, R. W. (2002) Behavior and physiology of mice lacking the GABAA receptor S subunit. Epilepsia 43, 3–8.

    Article  PubMed  CAS  Google Scholar 

  110. DeLorey, T. M., and Olsen, R. W. (1999) GABA and epileptogenesis: comparing gabrb3 gene-deficient mice with Angelman syndrome in man. Epilepsy Res. 36, 123–132.

    Article  PubMed  CAS  Google Scholar 

  111. Crestani, F., Lorez, M., Baer, K., et al. (1999) Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nature Neurosci. 2, 833–839.

    Article  PubMed  CAS  Google Scholar 

  112. Rudolph, U., Crestani, F., and Mohler, H. (2001) GABAA receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol. Sci. 22, 188–194.

    Article  PubMed  CAS  Google Scholar 

  113. Mohler, H., Crestani, F., and Rudolph, U. (2001) GABAA-receptor subtypes: a new pharmacology. Curr. Opin. Pharmacol. 1, 22–25.

    Article  PubMed  CAS  Google Scholar 

  114. Löw, K., Crestani, F., Keist, R., et al. (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131–134.

    Article  PubMed  Google Scholar 

  115. Rudolph, U., Crestani, F., Benke, D., et al. (1999) Benzodiazepine actions mediated by specific y-aminobutyric acid, receptor subtypes. Nature 401, 796–800.

    Article  PubMed  CAS  Google Scholar 

  116. McKernan, R. M., Rosahl, T. W., Reynolds, D. S., et al. (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor a1 subtype. Nature Neurosci. 3, 587–592.

    Article  PubMed  CAS  Google Scholar 

  117. Crestani, F., Assandri, R., Täuber, M., Martin, J. R., and Rudolph, U. (2002) Contribution of the al-GABAA receptor subtype to the pharmacological actions of benzodiazepine site inverse agonists. Neuropharmacology 43, 679–684.

    Article  PubMed  CAS  Google Scholar 

  118. Crestani, F., Low, K., Keist, R., Mandelli, M.-J., Mohler, H., and Rudolph, U. (2000) Molecular targets for the myorelaxant action of diazepam. Mol. Pharmacol. 59, 442–445.

    Google Scholar 

  119. Bohlhalter, S., Weinmann, O., Mohler, H., and Fritschy, J. M. (1996) Laminar compartmentalization of GABAA-receptor subtypes in the spinal cord. J. Neurosci. 16, 283–297.

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. Jean-Marc Fritschy
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Pharmacology, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark

    Arne Schousboe PhD, DSc

  2. Department of Medical Chemistry, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark

    Hans Bräuner-Osborne PhD, DSc

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science+Business Media New York

About this chapter

Cite this chapter

Fritschy, JM. (2004). In Vivo Function of GABAA Receptor Subtypes Unraveled With Mutant Mice. In: Schousboe, A., Bräuner-Osborne, H. (eds) Molecular Neuropharmacology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-672-0_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-672-0_5

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-384-8

  • Online ISBN: 978-1-59259-672-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation