Analysis of GABAA Receptor Function and Dissection of the Pharmacology of Benzodiazepines and General Anesthetics Through Mouse Genetics

Annual Review of Pharmacology and Toxicology

Volumn 44, Issue , 2004, Pages 475-498

  Rudolph, Uwe ^a   Möhler, Hanns ^a  

^a UNIVERSITY OF ZURICH   (Switzerland)

Author keywords

Anxiolysis; Diazepam; Etomidate; Knockin mice; Knockout mice

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; ANESTHETIC AGENT; BENZODIAZEPINE DERIVATIVE; DIAZEPAM; ENFLURANE; ETOMIDATE; HALOTHANE; PROPOFOL; RECEPTOR SUBUNIT; ZOLPIDEM; PROTEIN SUBUNIT;

ALERTNESS; ANXIETY DISORDER; DRUG RECEPTOR BINDING; EPILEPTOGENESIS; KNOCKOUT MOUSE; MEMORY; MOUSE; MOUSE STRAIN; MUSCLE TONE; NONHUMAN; POINT MUTATION; PRIORITY JOURNAL; PROTEIN ASSEMBLY; REVIEW; SYNAPTIC INHIBITION; TRANSCRIPTION REGULATION; ANIMAL; GENETICS; METABOLISM; MOUSE MUTANT;

ANESTHETICS, GENERAL; ANIMALS; BENZODIAZEPINES; MICE; MICE, KNOCKOUT; PROTEIN SUBUNITS; RECEPTORS, GABA-A;

EID: 1342344806     PISSN: 03621642     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.44.101802.121429     Document Type: Review

References (102)

1. Buzsaki G, Chrobak JJ. 1995. Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks. Curr. Opin. Neurobiol. 5:504-10
2. Paulsen O, Moser EI. 1998. A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends Neurosci. 21:273-78
3. Freund TF, Buzsaki G. 1996. Interneurons of the hippocampus. Hippocampus 6:347-470
4. Miles R. 2000. Perspectives: neurobiology. Diversity in inhibition. Science 287:244-46
5. Klausberger T, Roberts JD, Somogyi P. 2002. Cell type- and input-specific differences in the number and subtypes of synaptic GABA(A) receptors in the hippocampus. J. Neurosci. 22:2513-21
6. Klausberger T, Magill PJ, Marton LF, Roberts JD, Cobden PM, et al. 2003. Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo. Nature 421:844-48
7. Whittington MA, Traub RD, Jefferys JG. 1995. Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature 373:612-15
8. Whittington MA, Traub RD, Faulkner HJ, Stanford IM, Jefferys JG. 1997. Recurrent excitatory postsynaptic potentials induced by synchronized fast cortical oscillations. Proc. Natl. Acad. Sci. USA 94:12198-203
9. Buhl EH, Tamas G, Fisahn A. 1998. Cholinergic activation and tonic excitation induce persistent gamma oscillations in mouse somatosensory cortex in vitro. J. Physiol. 513(Pt. 1):117-26
10. Fisahn A, Pike FG, Buhl EH, Paulsen O. 1998. Cholinergic induction of network oscillations at 40 Hz in the hippocampus in vitro. Nature 394:186-89
11. Penttonen M, Kamondi A, Acsady L, Buzsaki G. 1998. Gamma frequency oscillation in the hippocampus of the rat: intracellular analysis in vivo. Eur. J. Neurosci. 10:718-28
12. Zhang Y, Perez Velazquez JL, Tian GF, Wu CP, Skinner FK, et al. 1998. Slow oscillations (
13. Traub RD, Draguhn A, Whittington MA, Baldeweg T, Bibbig A, et al. 2002. Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis. Rev. Neurosci. 13:1-30
14. McCormick DA, Bal T. 1997. Sleep and arousal: thalamocortical mechanisms. Annu. Rev. Neurosci. 20:185-215
15. Singer W, Gray CM. 1995. Visual feature integration and the temporal correlation hypothesis. Annu. Rev. Neurosci. 18:555-86
16. Laurent G. 1996. Dynamical representation of odors by oscillating and evolving neural assemblies. Trends Neurosci. 19:489-96
17. Engel AK, Fries P, Singer W. 2001. Dynamic predictions: oscillations and synchrony in top-down processing. Nat. Rev. Neurosci. 2:704-16
18. Traub RD, Whittington MA, Stanford IM, Jefferys JG. 1996. A mechanism for generation of long-range synchronous fast oscillations in the cortex. Nature 383:621-24
19. O'Keefe J, Recce ML. 1993. Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3:317-30
20. Csicsvari J, Hirase H, Czurko A, Mamiya A, Buzsaki G. 1999. Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat. J. Neurosci. 19:274-87
21. Maccaferri G, Roberts JD, Szucs P, Cottingham CA, Somogyi P. 2000. Cell surface domain specific postsynaptic currents evoked by identified GABAergic neurones in rat hippocampus in vitro. J. Physiol. 524(Pt. 1):91-116
22. Burgess N, Maguire EA, O'Keefe J. 2002. The human hippocampus and spatial and episodic memory. Neuron 35:625-41
23. Brun VH, Otnass MK, Molden S, Steffenach HA, Witter MP, et al. 2002. Place cells and place recognition maintained by direct entorhinal-hippocampal circuitry. Science 296:2243-46
24. Nyiri G, Freund TF, Somogyi P. 2001. Input-dependent synaptic targeting of alpha(2)-subunit-containing GABA(A) receptors in synapses of hippocampal pyramidal cells of the rat. Eur. J. Neurosci. 13:428-42
25. Pawelzik H, Hughes DI, Thomson AM. 2002. Physiological and morphological diversity of immunocytochemically defined parvalbumin- and cholecystokinin-positive interneurones in CA1 of the adult rat hippocampus. J. Comp. Neurol. 443:346-67
26. Brussaard AB, Kits KS, Baker RE, Willems WP, Leyting-Vermeulen JW, et al. 1997. Plasticity in fast synaptic inhibition of adult oxytocin neurons caused by switch in GABA(A) receptor subunit expression. Neuron 19:1103-14
27. A receptor desensitization kinetics and its role in synapse function in rat cortical neurons. J. Physiol. 522 (Pt 1):3-17
28. Juttner R, Meier J, Grantyn R. 2001. Slow IPSC kinetics, low levels of alpha1 subunit expression and paired-pulse depression are distinct properties of neonatal inhibitory GABAergic synaptic connections in the mouse superior colliculus. Eur. J. Neurosci. 13:2088-98
29. Vicini S, Ferguson C, Prybylowski K, Kralic J, Morrow AL, Homanics GE. 2001. GABA(A) receptor alpha1 subunit deletion prevents developmental changes of inhibitory synaptic currents in cerebellar neurons. J. Neurosci. 21:3009-16
30. Sur C, Wafford KA, Reynolds DS, Hadingham KL, Bromidge F, et al. 2001. Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice. J. Neurosci. 21:3409-18
31. Kralic JE, Korpi ER, O'Buckley TK, Homanics GE, Morrow AL. 2002. Molecular and pharmacological characterization of GABA(A) receptor alpha1 subunit knockout mice. J. Pharmacol. Exp. Ther. 302:1037-45
32. A receptor. J. Neurosci. 22:5572-80
33. A-receptor alpha-subunit is an essential pre-requisite for receptor formation in vivo. Neuroscience 81:1043-53
34. Fritschy JM, Johnson DK, Mohler H, Rudolph U. 1998. Independent assembly and subcellular targeting of GABA(A)-receptor subtypes demonstrated in mouse hippocampal and olfactory neurons in vivo. Neurosci. Lett. 249:99-102
35. A receptor subunits in cerebellar granule cells after the disruption of the alpha6 subunit gene. Eur. J. Neurosci. 11:1685-97
36. Uusi-Oukari M, Heikkila J, Sinkkonen ST, Makela R, Hauer B, et al. 2000. Long-range interactions in neuronal gene expression: evidence from gene targeting in the GABA(A) receptor beta2-alpha6-alpha1-gamma2 subunit gene cluster. Mol. Cell Neurosci. 16:34-41
37. A receptor alpha6 subunit gene inactivation inhibits delta subunit expression. J. Neurosci. 17:1350-62
38. Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, et al. 1997. Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Natl. Acad. Sci. USA 94:4143-48
39. Gunther U, Benson J, Benke D, Fritschy JM, Reyes G, et al. 1995. Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Proc. Natl. Acad. Sci. USA 92:7749-53
40. A receptors from mice lacking the 2 subunit. J. Physiol. 527(Pt. 1):11-31
41. A receptor subtypes requires the gamma 2 subunit and gephyrin. Nat. Neurosci. 1:563-71
42. Korpi ER, Mihalek RM, Sinkkonen ST, Hauer B, Hevers W, et al. 2002. Altered receptor subtypes in the forebrain of GABA(A) receptor delta subunit-deficient mice: recruitment of gamma 2 subunits. Neuroscience 109:733-43
43. Peng Z, Hauer B, Mihalek RM, Homanics GE, Sieghart W, et al. 2002. GABA(A) receptor changes in delta subunit-deficient mice: altered expression of alpha4 and gamma2 subunits in the forebrain. J. Comp. Neurol. 446:179-97
44. Goldstein PA, Elsen FP, Ying SW, Ferguson C, Homanics GE, Harrison NL. 2002. Prolongation of hippocampal miniature inhibitory postsynaptic currents in mice lacking the GABA(A) receptor alpha1 subunit. J. Neurophysiol. 88:3208-17
45. Kralic JE, O'Buckley TK, Khisti RT, Hodge CW, Homanics GE, Morrow AL. 2002. GABA(A) receptor alpha-1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 43:685-94
46. Reynolds DS, O'Meara GF, Newman RJ, Bromidge FA, Atack JR, et al. 2003. GABA(A) alpha 1 subunit knock-out mice do not show a hyperlocomotor response following amphetamine or cocaine treatment. Neuropharmacology 44:190-98
47. Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, et al. 1999. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401:796-800
48. A receptors reduces actions of alcohol and other drugs. J. Pharmacol. Exp. Ther. 304:30-36
49. Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, et al. 2002. Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc. Natl. Acad. Sci. USA 99:8980-85
50. Chambers MS, Atack JR, Broughton HB, Collinson N, Cook S, et al. 2003. Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition. J. Med. Chem. 46: 2227-40
51. A receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice. Eur. J. Neurosci. 11:233-40
52. Homanics GE, Ferguson C, Quinlan JJ, Daggett J, Snyder K, et al. 1997. Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol. Pharmacol. 51:588-96
53. Brickley SG, Revilla V, Cull-Candy SG, Wisden W, Farrant M. 2001. Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature 409:88-92
54. Culiat CT, Stubbs L, Nicholls RD, Montgomery CS, Russell LB, et al. 1993. Concordance between isolated cleft palate in mice and alterations within a region including the gene encoding the beta 3 subunit of the type A gamma-aminobutyric acid receptor. Proc. Natl. Acad. Sci. USA 90:5105-9
55. A receptor subunit genes is deleted in a neurological mutant of the mouse p locus. Nature 364:448-50
56. Culiat CT, Stubbs LJ, Woychik RP, Russell LB, Johnson DK, Rinchik EM. 1995. Deficiency of the beta 3 subunit of the type A gamma-aminobutyric acid receptor causes cleft palate in mice. Nat. Genet. 11:344-46
57. A receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J. Neurosci. 18:8505-14
58. Ugarte SD, Homanics GE, Firestone LL, Hammond DL. 2000. Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the beta3 subunit of the GABA(A) receptor. Neuroscience 95:795-806
59. Quinlan JJ, Homanics GE, Firestone LL. 1998. Anesthesia sensitivity in mice that lack the beta3 subunit of the gamma-aminobutyric acid type A receptor. Anesthesiology 88:775-80
60. Wong SM, Cheng G, Homanics GE, Kendig JJ. 2001. Enflurane actions on spinal cords from mice that lack the beta3 subunit of the GABA(A) receptor. Anesthesiology 95:154-64
61. Resnick A, Homanics GE, Jung BJ, Peris J. 1999. Increased acute cocaine sensitivity and decreased cocaine sensitization in GABA(A) receptor beta3 subunit knockout mice. J. Neurochem. 73:1539-48
62. Laposky AD, Homanics GE, Basile A, Mendelson WB. 2001. Deletion of the GABA(A) receptor beta 3 subunit eliminates the hypnotic actions of oleamide in mice. Neuroreport 12:4143-47
63. Huntsman MM, Porcello DM, Homanics GE, DeLorey TM, Huguenard JR. 1999. Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science 283:541-43
64. Baer K, Essrich C, Benson JA, Benke D, Bluethmann H, et al. 1999. Postsynaptic clustering of gamma-aminobutyric acid type A receptors by the gamma3 subunit in vivo. Proc. Natl. Acad. Sci. USA 96:12860-65
65. A-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat. Neurosci. 2:833-39
66. A receptor expressed in Xenopus oocytes requires 8 amino acids contained in the gamma 2L subunit. Neuron 7:27-33
67. Homanics GE, Harrison NL, Quinlan JJ, Krasowski MD, Rick CE, et al. 1999. Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the gamma2 subunit of the gamma-aminobutyrate type A receptor. Neuropharmacology 38:253-65
68. Quinlan JJ, Firestone LL, Homanics GE. 2000. Mice lacking the long splice variant of the gamma 2 subunit of the GABA(A) receptor are more sensitive to benzodiazepines. Pharmacol. Biochem. Behav. 66:371-74
69. A receptor gamma2S or gamma2L subunit isoforms. Eur. J. Neurosci. 12:2639-43
70. Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, et al. 1999. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc. Natl. Acad. Sci. USA 96:12905-10
71. Vicini S, Losi G, Homanics GE. 2002. GABA(A) receptor delta subunit deletion prevents neurosteroid modulation of inhibitory synaptic currents in cerebellar neurons. Neuropharmacology 43:646-50
72. Porcello DM, Huntsman MM, Mihalek RM, Homanics GE, Huguenard JR. 2003. Intact synaptic GABAergic inhibition and altered neurosteroid modulation of thalamic relay neurons in mice lacking delta subunit. J. Neurophysiol. 89:1378-86
73. A receptor delta subunit. J. Neurophysiol. 90:903-10
74. Bormann J. 2000. The 'ABC' of GABA receptors. Trends Pharmacol. Sci. 21:16-19
75. A receptors: classification on the basis of subunit structure and receptor function. Pharmacol. Rev. 50:291-313
76. McCall MA, Lukasiewicz PD, Gregg RG, Peachey NS. 2002. Elimination of the rho1 subunit abolishes GABA(C) receptor expression and alters visual processing in the mouse retina. J. Neurosci. 22:4163-74
77. A receptors is essential for benzodiazepine agonist binding. J. Biol. Chem. 267:1426-29
78. A receptors rendered diazepam-insensitive by point-mutated alpha-subunits. FEBS Lett. 431:400-4
79. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, et al. 2000. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat. Neurosci. 3:587-92
80. Löw K, Crestani F, Keist R, Benke D, Brünig I, et al. 2000. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131-34
81. Crestani F, Martin JR, Möhler H, Rudolph U. 2000. Mechanism of action of the hypnotic zolpidem in vivo. Br. J. Pharmacol. 131:1251-54
82. Crestani F, Assandri R, Tauber M, Martin JR, Rudolph U. 2002. Contribution of the alpha1-GABA(A) receptor subtype to the pharmacological actions of benzodiazepine site inverse agonists. Neuropharmacology 43:679-84
83. A receptor mutant mouse studies. Nat. Neurosci. 3:1059
84. Tobler I, Kopp C, Deboer T, Rudolph U. 2001. Diazepam-induced changes in sleep: role of the alpha 1 GABA(A) receptor subtype. Proc. Natl. Acad. Sci. USA 98:6464-69
85. A-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359:154-94
86. A-receptors: drug binding profile and distribution of receptors containing the alpha 2-subunit in situ. J. Recept. Res. 13:467-77
87. Crestani F, Low K, Keist R, Mandelli M, Möhler H, Rudolph U. 2001. Molecular targets for the myorelaxant action of diazepam. Mol. Pharmacol. 59:442-45
88. Collins I, Moyes C, Davey WB, Rowley M, Bromidge FA, 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. 45:1887-900
89. A receptor subtype. Eur. J. Neurosci. 17:2226-30
90. Sohal VS, Keist R, Rudolph U, Huguenard JR. 2003. Dynamic GABA(A) receptor subtype-specific modulation of the synchrony and duration of thalamic oscillations. J. Neurosci. 23:3649-57
91. Huerta PT, Sun LD, Wilson MA, Tonegawa S. 2000. Formation of temporal memory requires NMDA receptors within CA1 pyramidal neurons. Neuron 25:473-80
92. Krasowski MD, Harrison NL. 1999. General anaesthetic actions on ligand-gated ion channels. Cell Mol. Life Sci. 55:1278-303
93. Patel AJ, Honore E, Lesage F, Fink M, Romey G, Lazdunski M. 1999. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat. Neurosci. 2:422-26
94. Miralles CP, Li M, Mehta AK, Khan ZU, De Blas AL. 1999. Immunocytochemical localization of the beta(3) subunit of the gamma-aminobutyric acid(A) receptor in the rat brain. J. Comp. Neurol. 413:535-48
95. A receptor subunit mRNAs in neurons of the rat spinal cord and dorsal root ganglia. Neuroscience 42:497-507
96. Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, et al. 1997. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature 389:385-89
97. Belelli D, Lambert JJ, Peters JA, Wafford K, Whiting PJ. 1997. The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid. Proc. Natl. Acad. Sci. USA 94:11031-36
98. Siegwart R, Jurd R, Rudolph U. 2002. Molecular determinants for the action of general anesthetics at recombinant alpha(2)beta(3)gamma(2)gamma-aminobutyric acid(A) receptors. J. Neurochem. 80:140-48
99. Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, et al. 2003. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J. 17:250-52
100. Antognini JF, Schwartz K. 1993. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 79:1244-49
101. Rampil IJ. 1994. Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology 80:606-10
102. Mihalek RM, Bowers BJ, Wehner JM, Kralic JE, VanDoren MJ, et al. 2001. GABA(A)-receptor delta subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol Clin. Exp. Res. 25:1708-18