Cell and Tissue Research

, Volume 326, Issue 2, pp 505–516 | Cite as

GABAA receptor diversity and pharmacology



Because of its control of spike-timing and oscillatory network activity, γ-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. The recognition of GABAA receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing α1GABAA receptors have been found to mediate sedation, whereas those expressing α2GABAA receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic α5GABAA receptors. In addition, neurons expressing α3GABAA receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with α1GABAA receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABAA receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.


Gamma-aminobutyric acid Benzodiazepines Anxiety Learning and memory Critical period plasticity 


  1. Alger BE, Pitler TA (1995) Retrograde signaling at GABAA-receptor synapses in the mammalian CNS. Trends Neurosci 18:333–340PubMedCrossRefGoogle Scholar
  2. Atack JR, Hutson PH, Collinson N, Marchall G, Bentley G, Moyes C, Cook SM, Collins I, Wafford K, McKernan RM, Dawson GR (2005) Anxiogenic properties of an inverse agonist selective for α3 subunit-containing GABAA receptors. Br J Pharmacol 144:357–366PubMedCrossRefGoogle Scholar
  3. Atack JR, Wafford K, Tye SJ, Cook S, Sohal B, Pike A, Sur C, Melillo D, Bristow L, Bromidge F, et al (2006a) TPA023 an agonist selective for α2- and α3-containing GABAA receptors, is a non-sedating anxiolytic in rodents and primates. J Pharm Exp Ther 316:410–422CrossRefGoogle Scholar
  4. Atack JR, Wafford K, Tye SJ, Cook S, Sohal B, Pike A, Sur C, Melillo D, Bristow L, Bromidge F, et al (2006b) The in vivo properties of pagoclone in rat are most likely mediated by 5′-hydroxy pagoclone. Neuropharmacology (in press)Google Scholar
  5. Barnard EA, Skolnick P, Olsen RW, Möhler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (1998) Subtypes of γ-aminobutyric acidA receptors: classification on the bases of subunit structure and receptor function. Pharmacol Rev 50:291–313PubMedGoogle Scholar
  6. Belelli D, Lambert JJ (2005) Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 6:565–575PubMedCrossRefGoogle Scholar
  7. Benson J, Löw K, Keist R, Möhler H, Rudolph U (1998) Pharmacology of recombinant GABAA receptors rendered diazepam-insensitive by point-mutated α-subunits. FEBS Lett 431:400–404PubMedCrossRefGoogle Scholar
  8. Bianchi MT, McDonald RL (2003) Neurosteroids shift partial agonist activation of GABA(A) receptor channels from low- to high-efficacy gating patterns. J Neurosci 23:10934–10943PubMedGoogle Scholar
  9. Bormann J (2000) The “ABC” of GABA receptors. Trends Pharmacol Sci 21:16–19PubMedCrossRefGoogle Scholar
  10. Brickley SG, Cull-Candy SG, Farrant M (1996) Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J Physiol (Lond) 497:753–759Google Scholar
  11. Brickley SG, Revilla V, Cull-Candy SG, Wisden W, Farrant M (2001) Adaptive regulation of neuronal excitability by a voltage independent potassium conductance. Nature 409:88–92PubMedCrossRefGoogle Scholar
  12. Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA (2002) Pharmacological characterization of a novel cell line expressing human α4β3δ GABAA receptors. Br J Pharmacol 136:965–974PubMedCrossRefGoogle Scholar
  13. Brussaard AB, Herbison AE (2000) Long-term plasticity of postsynaptic GABAA-receptor function in the adult brain: insights from the oxytocin neurone. Trends Neurosci 23:190–195PubMedCrossRefGoogle Scholar
  14. Campagna JA, Miller KW, Forman SA (2003) Mechanisms of actions of inhaled anesthetics. N Engl J Med 348:2110–2124PubMedCrossRefGoogle Scholar
  15. Caulfield MP, Brown DA (1992) Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br J Pharmacol 106:231–232PubMedGoogle Scholar
  16. Chambers MS, Attack JR, Broughton HB, Collinson N, Cook S, Dawson GR, Hobbs SC, Marshall G, Maubach KA, Pillai GV, Reeve AJ, MacLeod AM (2003) Identification of a novel, selective GABAA α5 receptor inverse agonist which enhances cognition. J Med Chem 46:2227–2240PubMedCrossRefGoogle Scholar
  17. Chambers MS, Atack JR, Carling RW, Collinson N, Cook SM, Dawson GR, Ferris P, Hobbs SC, O’Connor D, Marshall G et al (2004) An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties. J Med Chem 47:5829–5832PubMedCrossRefGoogle Scholar
  18. Chevaleyre V, Castillo PE (2003) Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38:461–472PubMedCrossRefGoogle Scholar
  19. Cirone J, Rosahl TW, Reynolds DS, Newman RJ, O’Meara GF, Hutson PH, Wafford KA (2004) Gamma-aminobutyric acid type A receptor beta 2 subunit mediates the hypothermic effect of etomidate in mice. Anesthesiology 100:1438–1445PubMedCrossRefGoogle Scholar
  20. Collins I, Moyes C, Davey WB, Rowley M, Bromidge FA, Quirk K, et al (2002) 3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional delectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels. J Med Chem 45:1887–1900PubMedCrossRefGoogle Scholar
  21. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, et al (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the α5 subunit of the GABAA receptor. J Neurosci 22:5572–5580PubMedGoogle Scholar
  22. Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L, Bluethmann H, Möhler H, Rudolph U (2002) Trace fear conditioning involves hippocampal a5 GABAA receptors. Proc Natl Acad Sci USA 99:8980–8985PubMedCrossRefGoogle Scholar
  23. Dämgen K, Lüddens H (1999) Zaleplon diaplays a selecitvity to recombinant GABAA receptors different from zolpidem, zopiclone and benzodiazepines. Neurosci Res Comm 25:139–148CrossRefGoogle Scholar
  24. Dellini-Stula A, Berdah-Tordjman D (1996) Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia—a study group report. J Psychiatr Res 30:239–250CrossRefGoogle Scholar
  25. Devor A, Fritschy JM, Yarom Y (2001) Spatial distribution and subunit composition of GABAA receptors in the inferior olivary nucleus. J Neurophysiol 85:1686–1696PubMedGoogle Scholar
  26. Dias R, et al (2005) Evidence for a significant role of alpha3–containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines. J Neurosci 25:10682–10688PubMedCrossRefGoogle Scholar
  27. Engel AK, Fries P, Singer W (2001) Dynamic predictions: oscillations and synchrony in top-down processing. Nat Rev Neurosci 2:704–716PubMedCrossRefGoogle Scholar
  28. Ernst M, Brauchart D, Boresch S, Sieghart W (2003) Comparative modeling of GABAA receptors: limits, insights, future developments. J Neuroscience 4:933–943Google Scholar
  29. Fagiolini M, Hensch T (2000) Inhibitory threshold for critical-period activation in primary visual cortex. Nature 404:183–186PubMedCrossRefGoogle Scholar
  30. Fagiolini M, Fritschy JM, Löw K, Möhler H, Rudolph U, Hensch T (2004) Specific GABAA circuits for visual cortical plasticity. Science 303:1681–1683PubMedCrossRefGoogle Scholar
  31. Ferster D (2004) Blocking plasticity in the visual cortex. Science 303:1619–1621PubMedCrossRefGoogle Scholar
  32. Foeller E, Feldmann DE (2004) Synaptic basis for developmental plasticity in somatosensory cortex. Curr Opin Neurobiol 14:89–95PubMedCrossRefGoogle Scholar
  33. Foster AC, Pelleymounter MA, Cullen MJ, Lewis D, Joppa M, Chen TK, Bozigian HP, Gross RS, Gogas KR (2004) In vivo pharmacological characterization of indiplon, a novel pyrazolopyrimidine sedative-hypnotic. J Pharmacol Exp Ther 311:547–559PubMedCrossRefGoogle Scholar
  34. Freund TF, Buzsaki G (1996) Interneurons of the hippocampus. Hippocampus 6:345–470CrossRefGoogle Scholar
  35. Fritschy JM, Brünig I (2003) Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications. Pharmacol Ther 98:299–323PubMedCrossRefGoogle Scholar
  36. Fritschy JM, Möhler H (1995) GABAA receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J Comp Neurol 359:154–194PubMedCrossRefGoogle Scholar
  37. Fritschy JM, Crestani F, Rudolph U, Möhler H (2004) GABAA receptor subtypes with special reference to memory function and neurological disorders. In: Hensch TK, Fagiolini M (eds) Excitatory inhibitory balance: synapses, circuits and systems plasticity. Kluwer Academic/Plenum, New York, pp 215–228Google Scholar
  38. Gao B, Fritschy JM, Benke D, Möhler H (1993) Neuron-specific expression of GABAA receptor subtypes: differential associations of the α1- and α3-subunits with serotonergic and GABAergic neurons. Neuroscience 54:881–892PubMedCrossRefGoogle Scholar
  39. Geiger JR, Lubke J, Roth A, Frotscher M, Jonas P (1997) Submillisecond AMPA receptor-mediated signalling at a principal neuron-interneuron synapse. Neuron 18:1009–1023PubMedCrossRefGoogle Scholar
  40. Griebel G, Perrault G, Simiand J, Cohen C, Granger P, Depoortere H, Francon D, Avenet P, Schoemaker H, Evanno Y, et al (2003) SL651498, a GABAA receptor agonist with subtype-selective efficacy, as a potential treatment for generalized anxiety disorder and muscle spasms. CNS Drug Rev 9:3–20PubMedCrossRefGoogle Scholar
  41. Gupta A, Wang Y, Markam H (2000) Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science 287:273–278PubMedCrossRefGoogle Scholar
  42. Haefeli W, Martin JR, Schoch P (1990) Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol Sci 11:452–456CrossRefGoogle Scholar
  43. Harris KD, Henze DA, Hirase H, Leinekugel X, Dragoi G, Czurko A, Buzsaki G (2002) Spike train dynamics predicts theta-related phase precession in hippocampal pyramidal cells. Nature 417:738–741PubMedCrossRefGoogle Scholar
  44. Hauser J, Rudolph U, Keist R, Möhler H, Feldon J, Yee B (2005) Hippocampal α5 subunit containing GABAA receptors modulate expression of prepulse inhibition. Mol Psychiatry 10:201–207PubMedCrossRefGoogle Scholar
  45. Hensch TK (2005) Critical period plasticity in local cortical circuits. Nature Rev Neurosci 6:877–888CrossRefGoogle Scholar
  46. Hensch TK, Stryker MP (2004) Columnar architecture sculped by GABA circuits in developing cat visual cortex. Science 303:1678–1681PubMedCrossRefGoogle Scholar
  47. Huckle R (2004) Gaboxadol Lundbeck/Merck. Curr Opin Investig Drugs 5:766–773PubMedGoogle Scholar
  48. Huntsmann MM, Porcello DM, Homanics GE, DeLorey TM, Huguenard JR (1999) Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science 283:541–543CrossRefGoogle Scholar
  49. Hutcheon B, Morley P, Poulter MO (2000) Developmental change in GABAA receptor desensitization kinetics and its role in synapse function in rat cortical neurons. J Pysiol (Lond) 522:3–17CrossRefGoogle Scholar
  50. Jüttner R, Meier J, Grantyn R (2001) Slow IPSC kinetics, low levels of α1 subunit expression and paired-pulse depression are distinct properties of neonatal inhibitory GABAergic synaptic connections in the mouse superior colliculus. Eur J Neurosci 13:2088–2098PubMedCrossRefGoogle Scholar
  51. Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg M, Vogt KE, Ledermann B, Antkowiak B, et al (2003) General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J 17:250–252PubMedGoogle Scholar
  52. Kandler K (2004) Activity-dependent organization of inhibitory circuits: lessons from the auditory system. Curr Opin Neurobiol 14:96–104PubMedCrossRefGoogle Scholar
  53. Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, La Rana G, Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81PubMedCrossRefGoogle Scholar
  54. Katona I, Sperlagh B, Sik A, Käfalvi A, Vizi ES, Mackie K, Freund TF (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19:4544–4558PubMedGoogle Scholar
  55. Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N, Freund TF (2001) Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci 21:9506–9518PubMedGoogle Scholar
  56. Klausberger T, Roberts JD, Somogyi P (2002) Cell type- and input-specific differences in the number and subtypes of synaptic GABAA receptors in the hippocampus. J Neurosci 22:2513–2521PubMedGoogle Scholar
  57. Klausberger T, Magill PJ, Marton LF, Roberts JDB, Cobden PM, Buzsaki G, Somogyi P (2003) Brain state- and cell type-specific firing of hippocampal interneurons in vivo. Nature 421:844–848PubMedCrossRefGoogle Scholar
  58. Kopp C, Rudolph U, Tobler I (2004a) Sleep EEG changes after zolpidem in mice. Neuroreport 15:2299–2302PubMedCrossRefGoogle Scholar
  59. Kopp C, Rudolph U, Löw K, Tobler I (2004b) Modulation of rhythmic brain activity by diazepam: GABA(A) receptor subtype and state specificity. Proc Natl Acad Sci USA 101:3674–3679PubMedCrossRefGoogle Scholar
  60. Krasowski MD, Koltchine VV, Rick CE, Ye Q, Finn SE, Harrison NL (1998) Propofol and other intravenous anesthetics have sites of action on the gamma-aminobutyric acid type A receptor distinct from that for isoflurane. Mol Pharmacol 53:530–538PubMedGoogle Scholar
  61. Kreitzer AC, Regehr WG (2001a) Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29:717–727PubMedCrossRefGoogle Scholar
  62. Kreitzer AC, Regehr WG (2001b) Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J Neurosci 21:RC174PubMedGoogle Scholar
  63. Lambert S, Arras M, Vogt KE, Rudolph U (2005) Isoflurane-induced surgical tolerance mediated only in part by beta3-containing GABA(A) receptors. Eur J Pharmacol 516:23–27PubMedCrossRefGoogle Scholar
  64. Lancel M, Steiger A (1999) Sleep and its modulation by drugs that affect GABAA receptor function. Angew Chem Int Ed 111:2852–2864CrossRefGoogle Scholar
  65. Langen B, Egerland U, Bernoster K, Dost R, Unverferth K, Rundfeldt C (2005) Characterization in rats of the anxiolytic potential of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a new agonist at the benzodiazepine binding site of the GABAA receptor. J Pharmacol Exp Ther 314:717–724PubMedCrossRefGoogle Scholar
  66. Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324PubMedCrossRefGoogle Scholar
  67. Liao M, Sonner JM, Jurd R, Rudolph U, Borghese CM, Harris RA, Laster MJ, Eger EI 2nd (2005) Beta3-containing gamma-aminobutyric acidA receptors are not major targets for the amnesic and immobilizing actions of isoflurane. Anesth Analg 101:412–418PubMedCrossRefGoogle Scholar
  68. Lippa A, Czobor P, Stark J, Beer B, Kostakis E, Gravielle M, Bandyopadhyay S, Russek SJ, Gibbs TT, Farb DH, Skolnick P (2005) Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator. Proc Natl Acad Sci USA 102:7380–7385PubMedCrossRefGoogle Scholar
  69. Llano I, Leresche N, Marty A (1991) Calcium entry increases the sensitivity of cerebellar Purkinje cells to applied GABA and decreases inhibitory synaptic currents. Neuron 6:565–574PubMedCrossRefGoogle Scholar
  70. Löw K, Crestani F, Keist R, Benke D, Brunig I, Benson JA, Fritschy JM, Rulicke T, Bluethmann H, Möhler H, Rudolph U (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131–134PubMedCrossRefGoogle Scholar
  71. Maejima T, Ohno-Shosaku T, Kano M (2001) Endogenous cannabinoid mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29:729–738PubMedCrossRefGoogle Scholar
  72. Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silbergerb G, Wu C (2004) Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 10:793–807CrossRefGoogle Scholar
  73. Marowsky A, Fritschy JM, Vogt KE (2004) Functional mapping of GABAA receptor subtypes in the amygdala. Eur J Neurosci 20:1281–1289PubMedCrossRefGoogle Scholar
  74. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534PubMedCrossRefGoogle Scholar
  75. Martina M, Schultz JH, Ehmke H, Monyer H, Jonas P (1998) Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus. J Neurosci 18:1811–1825Google Scholar
  76. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nat Neurosci 3:587–592PubMedCrossRefGoogle Scholar
  77. Metha MR, Lee AK, Wilson MA (2002) Role of experience and oscillations in transforming a rate code into a temporal code. Nature 417:741–746CrossRefGoogle Scholar
  78. Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, et al (1997) Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature 389:385–389PubMedCrossRefGoogle Scholar
  79. Mody I, Pearce RA (2004) Diversity of inhibitory neurotransmission through GABA(A) receptors. Trends Neurosci 27:569–575PubMedCrossRefGoogle Scholar
  80. Möhler H (2001) Functions of GABA receptors: pharmacology and pathophysiology. In: Möhler H (ed) Pharmacology of GABA and glycine neurotransmission. Springer, Berlin Heidelberg New York, pp 101–116Google Scholar
  81. Möhler H (2002) Pathophysiological aspects of diversity in neuronal inhibition: a new benzodiazepine pharmacology. Dialogues Clin Neurosci 4:261–269Google Scholar
  82. Möhler H, Benke D, Fritschy JM, Benson J (2000) The benzodiazepine site of GABAA receptors, In: Martin DL, Olsen RW (eds) GABA in the nervous system: the view at fifty years. Lippincott, Philadelphia, pp 97–112Google Scholar
  83. Möhler H, Fritschy JM, Rudolph U (2002) A new benzodiazepine pharmacology. J Pharm Exptl Ther 300:2–8CrossRefGoogle Scholar
  84. Möhler H, Fritschy JM, Vogt K, Crestani F, Rudolph U (2005) Pathophysiology and pharmacology of GABAA receptors. In: Holsboer F, Ströhle A (eds) Anxiety and anxiolytic drugs. Handbook of experimental pharmacology, vol 169. Springer, Berlin Heidelberg New York, pp 225–247Google Scholar
  85. Monyer H, Markram H (2004) Interneuron Diversity series: Molecular and genetic tools to study GABAergic interneuron diversity and function. Trends Neurosci 27:90–97PubMedCrossRefGoogle Scholar
  86. Moss SJ, Smart TG (2001) Constructing inhibitory synapses. Nat Rev Neurosci 2:240–250PubMedCrossRefGoogle Scholar
  87. Navarro JF, Buron E, Martin-Lopez M (2002) Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABA(A) receptors which contain the alpha-5 subunit, in the elevated plus-maze test. Prog Neuropsychopharmacol Biol Psychiatry 26:1389–1392PubMedCrossRefGoogle Scholar
  88. Navarro JF, Buron E and Martin-Lopez M (2004) Behavioral profile of L-655 708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the α5 subunit in social encounters between male mice. Aggress Behav 30:319–325CrossRefGoogle Scholar
  89. Nusser Z, Sieghart W, Stephenson FA, Somogyi P (1996) The α6 subunit of the GABAA receptor is concentrated in both inhibitory and excitatory synapses on cerebellar granule cells. J Neurosci 16:103–114PubMedGoogle Scholar
  90. Nusser Z, Sieghart W and Somogyi P (1998) Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J Neurosci 18:1693–1703PubMedGoogle Scholar
  91. Nyíri G, Freund TF and Somogyi P (2001) Input-dependent synaptic targeting of a2 subunit containing GABAA receptors in hippocampal pyramidal cells of the rat. Eur J Neurosci 13:428–442PubMedCrossRefGoogle Scholar
  92. O’Keefe J, Nadel L (1978) The hippocampus as a cognitive map. Clarendon, Oxford, pp 477–543Google Scholar
  93. O’Keefe J, Recce ML (1993) Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3:317–330PubMedCrossRefGoogle Scholar
  94. Paulsen O, Moser EI (1998) A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends Neurosci 21:273–278PubMedCrossRefGoogle Scholar
  95. Pawelzik H, Hughes DI, Thomson AM (2002) Physiological and morphological diversity of immunocytochemically defined parvalbumin- and cholecystokinin-positive interneurons in CA1 of the adult rat hippocampus. J Comp Neurol 443:346–367PubMedCrossRefGoogle Scholar
  96. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000) GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101:815–850PubMedCrossRefGoogle Scholar
  97. Pitler TA, Alger BE (1992) Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells. J Neurosci 12:4122–4132PubMedGoogle Scholar
  98. Pitler TA, Alger BE (1994) Depolarization-induced suppression of GABAergic inhibition in rat hippocampal pyramidal cells: G protein involvement in a presynaptic mechanism. Neuron 13:1447–1455PubMedCrossRefGoogle Scholar
  99. Pöltl A, Hauer B, Fuchs K, Tretter V, Sieghart W (2003) Subunit composition and quantitative importance of GABAA receptors subtypes in the cerebellum of mouse and rat. J Neurochem 87:1444–1455PubMedCrossRefGoogle Scholar
  100. Represa A, Ben-Ari Y (2005) Trophic actions of GABA on neuronal develpment. Trends Neurosci 28:278–283PubMedCrossRefGoogle Scholar
  101. Reynolds DS, Rosahl TW, Cirone J, O’Meara GF, Haythornthwaite A, Newman RJ, Myers J, Sur C, Howell O, Rutter AR, et al (2003) Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms. J Neurosci 23:8608–8617PubMedGoogle Scholar
  102. Rijnsoever C van, Tauber M, Choulli MK, Keist R, Rudolph U, Möhler H, Fritschy JM, Crestani F (2004) Requirement of α5 GABAA receptors for the development of tolerance to the sedative action of diazepam in mice. J Neurosci 24:6785–6790PubMedCrossRefGoogle Scholar
  103. Rudolph U, Antkowiak B (2004) Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci 5:709–720PubMedCrossRefGoogle Scholar
  104. Rudolph U, Möhler H (2004) Analysis of GABAA receptor function and dissection of pharmacology of benzodiazepines and general anaesthetics by mouse genetics. Annu Rev Pharmacol Toxicol 44:475–498PubMedCrossRefGoogle Scholar
  105. Rudolph U, Möhler H (2006) GABA-based therapeutic approaches: GABAA receptor subtype functions. Curr Opin Pharmacol 6:18–23PubMedCrossRefGoogle Scholar
  106. Rudolph U, Crestani F, Benke D, Brünig I, Benson J, Fritschy JM, Martin JR, Bluethmann H, Möhler H (1999) Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 401:796–800PubMedCrossRefGoogle Scholar
  107. Sieghart W, Sperk G (2002) Subunit composition, distribution and function of GABAA receptor subtypes. Curr Top Med Chem 2:795–816PubMedCrossRefGoogle Scholar
  108. Skaggs WE, McNaughton BL, Wilson MA, Barnes CA (1996) Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus 6:149–172PubMedCrossRefGoogle Scholar
  109. Sternfeld F, Carling RW, Jelley RA, Ladduwahetty T, Merchant KJ, Moore KW, Reeve AJ, Street LJ, O’Connor D, Sohal B, et al (2004) Selective, orally active gamma-amonobutyric acidA alpha5 receptor inverse agonists as cognition enhancers. J Med Chem 47:2176–2179PubMedCrossRefGoogle Scholar
  110. Storustovu S, Ebert B (2003) Gaboxadol: in vitro interaction studies with benzodiazepines and ethanol suggest functional selectivity. Eur J Pharmacol 467:49–56PubMedCrossRefGoogle Scholar
  111. Tobler I, Kopp C, Deboer T, Rudolph U (2001) Diazepam-induced changes in sleep: role of the α1GABAA receptor subtype. Proc Natl Acad Sci USA 98:6464–6469PubMedCrossRefGoogle Scholar
  112. Traub RD, Draguhn A, Whittington MA, Baldeweg T, Bibbig A, Buhl EH, Schmitz D (2002) Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis. Rev Neurosci 13:1–30PubMedGoogle Scholar
  113. Vicini S, Ferguson C, Prybylowski K, Kralic J, Morrow AL, Homanics GE (2001) GABAA receptor α1 subunit deletion prevents developmental changes of inhibitory synaptic currents in cerebellar neurons. J Neurosci 21:3009–3016PubMedGoogle Scholar
  114. Vincent P, Marty A (1993) Neighboring cerebellar Purkinje cell communicate via retrograde inhibition of common presynaptic interneurons. Neuron 11:885–893PubMedCrossRefGoogle Scholar
  115. Wallner M, Hanchar HJ, Olsen RW (2003) Ethanol enhances alpha4 beta3 delta and alpha6 beta3 delta gamma-aminobutyric acid type A receptors at low concentration known to affect humans. Proc Natl Acad Sci USA 100:15218–15223PubMedCrossRefGoogle Scholar
  116. Whiting PJ (2003) The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Dev 6:648–655Google Scholar
  117. Whiting P, Wafford KA, McKernan RM (2000) Pharmacologic subtypes of GABAA receptors based on subunit composition In: Martin DL, Olsen RW (eds) GABA in the nervous system: the view at fifty years. Lippincott, Philadelphia, pp 113–126Google Scholar
  118. Wiesel TN, Hubel DH (1963) Single cell responses in striate cortex of kittens deprived of vision in one eye. J Neurophysiol 26:1003–1017PubMedGoogle Scholar
  119. Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588–92 [erratum appears in Nature 2001 411:974]PubMedCrossRefGoogle Scholar
  120. Yee BK, Hauser J, Dolgov VV, Keist R, Möhler H, Rudolph U, Feldon J (2004) GABA receptors containing the α5 subunit mediate the trance effect in aversive and appetitive conditioning and extinction of conditioned fear. Eur J Neurosci 20:1928–1936PubMedCrossRefGoogle Scholar
  121. Yee BK, et al (2005) A schizophrenia-related sensorimotor deficit links α3-containing GABAA receptors to a dopamine hyperfunction. Proc Natl Acad Sci USA 102:17154–17159PubMedCrossRefGoogle Scholar
  122. Zeller A, Arras M, Lazaris A, Jurd R, Rudolph U (2005) Distinct molecular targets for the central respiratory and cardiac actions of the general anesthetics etomidate and propofol. FASEB J 12:1677–1679Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Institute of Pharmacology and Department of Chemistry and Applied BiosciencesUniversity and ETH ZurichZürichSwitzerland

Personalised recommendations