, Volume 230, Issue 2, pp 151–188 | Cite as

Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

  • Chase Matthew Carver
  • Doodipala Samba ReddyEmail author



Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal γ-aminobutyric acid (GABA) type A (GABAA) receptors are one of the prime molecular targets of neurosteroids.


This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABAA receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABAA receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABAA receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABAA receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior.


The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABAA receptors provides many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions.


GABA GABAA receptor Neurosteroid Allopregnanolone δ-Subunit Tonic inhibition Phasic inhibition Extrasynaptic receptors 



3α-Hydroxysteroid oxidoreductase




Allopregnanolone (3α-hydroxy-5α-pregnan-20-one)


Cerebellar granule cell


Central nervous system


Dentate gyrus granule cell


Dehydroepiandrosterone sulfate


GABAA receptor-associated protein


Inhibitory postsynaptic current






Pregnenolone sulfate


Traumatic brain injury




Allotetrahydrodeoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one)




Temporal lobe epilepsy


Translocator protein



This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke Grants NS051398, NS071597, and NS076426 (to D.S.R.). We thank Drs. William Griffith and Gerald Frye for comments on the manuscript. The authors would like to thank Xin Wu for technical help with illustrations.


  1. Abramian AM, Comenencia-Ortiz E, Vithlani M, Tretter EV, Sieghart W, Davies PA, Moss SJ (2010) Protein kinase C phosphorylation regulates membrane insertion of GABAA receptor subtypes that mediate tonic inhibition. J Biol Chem 285:41795–41805PubMedGoogle Scholar
  2. Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (2006) Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci U S A 103:14602–14607PubMedGoogle Scholar
  3. Akk G, Bracamontes J, Steinbach JH (2001) Pregnenolone sulfate block of GABAA receptors: mechanism and involvement of a residue in the M2 region of the α-subunit. J Physiol 532:673–684PubMedGoogle Scholar
  4. Akk G, Covery DF, Evers AS, Steinbach JH, Zorumski CF, Mennerick S (2009) The influence of the membrane on neurosteroid actions at GABAA receptors. Psychoneuroendocrinology 34S:S59–S66Google Scholar
  5. Akk G, Shu H, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (2005) Neurosteroid access to the GABAA receptor. J Neurosci 25:11605–11613PubMedGoogle Scholar
  6. Atack JR, Bayley PJ, Seabrook GR, Wafford KA, McKernan RM, Dawson GR (2006) L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors. Neuropharmacology 51:1023–1029PubMedGoogle Scholar
  7. Attwell D, Barbour B, Szatkowski M (1993) Nonvesicular release of neurotransmitter. Neuron 11:401–407PubMedGoogle Scholar
  8. Bai D, Zhu G, Pennefather P, Jackson MF, Macdonald JF, Orser BA (2001) Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by γ-aminobutyric acidA receptors in hippocampal neurons. Mol Pharmacol 59:814–824PubMedGoogle Scholar
  9. Baker C, Sturt BL, Bamber BA (2010) Multiple roles for the first transmembrane domain of GABAA receptor subunits in neurosteroid modulation and spontaneous channel activity. Neurosci Lett 473:242–247PubMedGoogle Scholar
  10. Barha CK, Ishrat T, Epp JR, Galea LA, Stein DG (2011) Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury. Exp Neurobiol 231:72–81Google Scholar
  11. Barmashenko G, Hefft S, Aertsen A, Kirschstein T, Kohling R (2011) Positive shifts of the GABAA receptor reversal potential due to altered chloride homeostasis is widespread after status epilepticus. Epilepsia 52:1570–1578PubMedGoogle Scholar
  12. Bateson AN (2002) Basic pharmacological mechanisms involved in benzodiazepine tolerance and withdrawal. Curr Pharm Des 8:5–21Google Scholar
  13. Baulieu EE (1981) Steroid hormones in the brain: several mechanisms? In: Fuxe F, Gustafsson JA, Wetterberg L (eds) Steroid hormone regulation of the brain. Pergamon, Oxford, pp 3–14Google Scholar
  14. Baumann SW, Baur R, Sigel E (2002) Forced subunit assembly in α1β2γ2 GABAA receptors. Insight into the absolute arrangement. J Biol Chem 277:46020–46025PubMedGoogle Scholar
  15. Baumann SW, Baur R, Sigel E (2003) Individual properties of the two functional agonist sites in GABAA receptors. J Neurosci 23:11158–11166PubMedGoogle Scholar
  16. Benson JA, Löw K, Keist R, Mohler H, Rudolph U (1998) Pharmacology of recombinant gamma-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated alpha-subunits. FEBS Lett 431:400–404PubMedGoogle Scholar
  17. Belelli D, Bolger MB, Gee KW (1989) Anticonvulsant profile of the progesterone metabolite 5α-pregnan-3α-ol-20-one. Eur J Pharmacol 166:325–329PubMedGoogle Scholar
  18. Belelli D, Casula A, Ling A, Lambert JJ (2002) The influence of subunit composition on the interaction of neurosteroids with GABAA receptors. Neuropharmacology 43:651–661PubMedGoogle Scholar
  19. Belelli D, Harrison NL, Maguire J, Macdonald RL, Walker MC, Cope DW (2009) Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci 29:12757–12763PubMedGoogle Scholar
  20. Belelli D, Lambert JL (2005) Neurosteroids: endogenous regulators of the GABAA receptor. Nat Rev Neurosci 6:565–575PubMedGoogle Scholar
  21. Benke D, Michel C, Mohler H (1997) GABAA receptors containing the α4 subunit: prevalence, distribution, pharmacology, and subunit architecture in situ. J Neurochem 69:806–814PubMedGoogle Scholar
  22. Bianchi MT, Haas KF, Macdonald RL (2001) Structural determinants of fast desensitization and desensitization–deactivation coupling in GABAA receptors. J Neurosci 21:1127–1136PubMedGoogle Scholar
  23. Bianchi MT, Haas KF, Macdonald RL (2002) α1 and α6 subunits specify distinct desensitization, deactivation and neurosteroid modulation of GABAA receptors containing the δ subunit. Neuropharmacology 43:492–502PubMedGoogle Scholar
  24. Bianchi MT, Macdonald RL (2003) Neurosteroids shift partial agonist activation of GABAA receptor channels from low- to high-efficacy gating patterns. J Neurosci 23:10934–10943PubMedGoogle Scholar
  25. Biggio G, Follesa P, Sanna E, Purdy RH, Concas A (2001) GABAA-receptor plasticity during long-term exposure to and withdrawal from progesterone. Int Rev Neurobiol 46:207–241PubMedGoogle Scholar
  26. Biggio F, Gorini G, Caria S, Murru L, Mostallino MC, Sanna E, Follesa P (2006) Plastic neuronal changes in GABAA receptor gene expression induced by progesterone metabolites—in vitro molecular and functional studies. Pharm Biochem Behav 84:545–554Google Scholar
  27. Boehm SL 2nd, Homanics GE, Blednov YA, Harris RA (2006) δ-Subunit containing GABAA receptor knockout mice are less sensitive to the actions of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol. Eur J Pharmacol 541:158–162PubMedGoogle Scholar
  28. Bogdanov Y, Michels G, Armstrong-Gold C, Haydon PG, Lindstrom J, Pangalos M, Moss SJ (2006) Synaptic GABAA receptors are directly recruited from their extrasynaptic counterparts. EMBO J 25:4381–4389PubMedGoogle Scholar
  29. Bonin RP, Martin LJ, MacDonald JF, Orser BA (2007) α5GABAA receptors regulate the intrinsic excitability of hippocampal pyramidal neurons. J Neurophysiol 98:2244–2254PubMedGoogle Scholar
  30. Bosman LW, Rosahl TW, Brussard AB (2002) Neonatal development of the rat visual cortex: synaptic function of GABAA receptor α subunits. J Physiol 545(Pt 1):169–181PubMedGoogle Scholar
  31. Bracamontes J, McCollum M, Esch C, Li P, Ann J, Steinbach JH, Akk G (2011) Occupation of either site for the neurosteroid allopregnanolone potentiates the opening of the GABAA receptor induced from either transmitter binding site. Mol Pharmacol 80:79–86PubMedGoogle Scholar
  32. Bright DP, Renzi M, Bartram J, McGee TP, MacKinzie G, Hosie AM, Farrant M, Brickley SG (2011) Profound desensitization by ambient GABA limits activation of δ-containing GABAA receptors during spillover. J Neurosci 31:753–763PubMedGoogle Scholar
  33. Briyal S, Reddy DS (2007) Antiepileptic efficacy of the delta-subunit-preferring GABAA receptor agonist gaboxadol on spontaneous recurrent seizures in a rat model of temporal lobe epilepsy. Soc Neurosci Abst 24(375.22):36Google Scholar
  34. Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Kelly ME, Coulter DA (2001) γ-Aminobutyric acidA receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development. J Neurochem 77:1266–1278PubMedGoogle Scholar
  35. 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 136:965–974PubMedGoogle Scholar
  36. Brussaard AB, Kits KS, Baker RE, Willems WP, Leyting-Vermeulen JW, Voorn P, Smit AB, Bicnell RJ, Herbison AE (1997) Plasticity in fast synaptic inhibition of adult oxytocin neurons caused by switch in GABAA receptor subunit expression. Neuron 19:1103–1114PubMedGoogle Scholar
  37. Brussaard AB, Koksma JJ (2003) Conditional regulation of neurosteroid sensitivity of GABAA receptors. Ann N Y Acad Sci 1007:29–36PubMedGoogle Scholar
  38. Brussaard AB, Herbison AE (2000) Long-term plasticity of postsynaptic GABAA receptor function in the adult brain: insights from oxytocin neurone. Trends Neurosci 23:190–195PubMedGoogle Scholar
  39. Buhr A, Wagner FK, Sieghart W, Sigel E (2001) Two novel residues in M2 of the γ-aminobutyric acid type A receptor affecting gating by GABA and picrotoxin affinity. J Biol Chem 276:7775–7781PubMedGoogle Scholar
  40. Calza A, Sogliano C, Santoru F, Marra C, Angioni MM, Mostallino MC, Biggio G, Concas A (2010) Neonatal exposure to estradiol in rats influences neuroactive steroid concentrations, GABAA receptor expression, and behavioral sensitivity to anxiolytic drugs. J Neurochem 113:1285–1295PubMedGoogle Scholar
  41. Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newll JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA et al (2004) Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by alpha5 subunit-containing gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci U S A 101:3662–3667PubMedGoogle Scholar
  42. Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW (1997) Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor. J Pharmacol Exp Ther 280:1284–1295PubMedGoogle Scholar
  43. Cavelier P, Hamann M, Rossi D, Mobbs P, Attwell D (2005) Tonic excitation and inhibition of neurons: ambient transmitter sources and computational consequences. Prog Biohphys Mol Biol 87:3–16Google Scholar
  44. Chandra D, Halonen LM, Linden AM, Procaccini C, Hellsten K, Homanics GE, Korpi ER (2010) Prototypic GABAA receptor agonist muscimol acts preferentially through forebrain high-affinity binding sites. Neuropsychopharmacology 35:999–1007PubMedGoogle Scholar
  45. Chandra D, Jia F, Liang J, Peng Z, Suryanarayanan A, Werner DF, Spigelman I, Houser CR, Olsen RW, Harrison NL et al (2006) GABAA receptor α4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol. Proc Natl Acad Sci U S A 103:15230–15235PubMedGoogle Scholar
  46. Chen ZW, Manion B, Townsend RR, Reichert DE, Covey DF, Steinbach JH, Sieghart W, Fuchs K, Evers AS (2012) Neurosteroid analog photolabeling of a site in the third transmembrane domain of the β3 subunit of the GABAA receptor. Mol Pharmacol 82:408–419PubMedGoogle Scholar
  47. Cherubini E, Gaiarsa JL, Ben-Ari Y (1991) GABA: an excitatory transmitter in early postnatal life. Trends Neurosci 14:515–519PubMedGoogle Scholar
  48. Chisari M, Eisenman LN, Krishnan K, Bandyopadhyaya AK, Wang C, Taylor A, Benz A, Covey DF, Zorumski CF, Mennerick S (2009) The influence of neuroactive steroid lipophilicity on GABAA receptor modulation: evidence for a low0affinity interaction. J Neurophysiol 102:1254–1264PubMedGoogle Scholar
  49. Chisari M, Eisenman LN, Covey DF, Mennerick S, Zorumski CF (2010) The sticky issue of neurosteroids and GABA-A receptors. Trends Neurosci 33:299–306PubMedGoogle Scholar
  50. Chiu CS, Brickley S, Jensen K, Southwell A, Mckinney S, Cull-Candy S, Mody I, Lester HA (2005) GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci 25:3234–3245PubMedGoogle Scholar
  51. Citraro R, Russo E, Di Paola ED, Ibbadu GF, Gratteri S, Marra R, De Sarro G (2006) Effects of some neurosteroids injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy. Neuropharmacology 50:1059–1071PubMedGoogle Scholar
  52. Clarke RS, Dundee JW, Carson IW (1973) Proceedings: a new steroid anaesthetic-althesin. Proc R Soc Med 66:1027–1030PubMedGoogle Scholar
  53. Cohen AS, Lin DD, Quirk GL, Coulter DA (2003) Dentate granule cell GABAA receptors in epileptic hippocampus: enhanced synaptic efficacy and altered pharmacology. Eur J Neurosci 17:1607–1616PubMedGoogle Scholar
  54. Compagnone NA, Mellon SH (2000) Neurosteroids: biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol 21:1–56PubMedGoogle Scholar
  55. Concas A, Mostallino MC, Porcu P, Follesa P, Barbaccia ML, Trabucchi M, Purdy RH, Grisenti P, Biggio G (1998) Role of brain allopregnanolone in the plasticity of γ-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery. Proc Natl Acad Sci U S A 95:13284–13289PubMedGoogle Scholar
  56. Coulter DA, Carlson GC (2007) Functional regulation of the dentate gyrus by GABA-mediated inhibition. Prog Brain Res 163:235–243PubMedGoogle Scholar
  57. Covey DF, Nathan D, Kalkbrenner M, Nilsson KR, Hu Y, Zorumsk CF, Evers AS (2000) Enantioselectivity of pregnanolone-induced γ-aminobutyric acidA receptor modulation and anesthesia. J Pharm Exp Ther 293:1009–1116Google Scholar
  58. Crawley JN, Glowa JR, Majewska MD, Paul SM (1986) Anxiolytic activity of endogenous adrenal steroid. Brain Res 398:382–385Google Scholar
  59. Demarque M, Represa A, Becq H, Khalilov I, Ben-Ari Y, Aniksztejin L (2002) Paracrine intracellular communication by a Ca2+- and SNARE-independent release of GABA and glutamate prior to synapse formation. Neuron 36:1051–1061PubMedGoogle Scholar
  60. Derry JMC, Dunn SMJ, Davies M (2004) Identification of a residue in the γ-aminobutyric acid type A receptor α subunit that differentially affects diazepam-sensitive and -insensitive benzodiazepine site binding. J Neurochem 88:1431–1438PubMedGoogle Scholar
  61. Devaud LL, Purdy RH, Finn DA, Morrow AL (1996) Sensitization of γ-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal. J Pharm Exp Ther 278:510–517Google Scholar
  62. Diaz MR, Wadleigh A, Hughes BA, Woodward JJ, Valenzuela CF (2012) Bestrophin1 channels are insensitive to ethanol and do not mediate tonic GABAergic currents in cerebellar granule cells. Front Neurosci 5:148PubMedGoogle Scholar
  63. Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, Jenkins M, Petrou S, Sutherland GR, Scheffer IE et al (2004) GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet 13:1315–1319PubMedGoogle Scholar
  64. Do Rego JL, Seong JY, Burel D, Leprince J, Luu-The V, Tsutsui K, Tonon MC, Pelletier G, Vaudry H (2009) Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front Neuroendocrinol 30:259–301PubMedGoogle Scholar
  65. Duveau V, Laustela S, Barth L, Gianolini F, Vogt KE, Keist R, Chandra D, Homanics GE, Rudolph U, Fritschy JM (2011) Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis. Eur J Neurosci 34:362–373PubMedGoogle Scholar
  66. Ebert B, Thompson SA, Saounatsou K, McKernan R, Krogsgaard-Larsen P, Wafford KA (1997) Differences in agonist/antagonist binding affinity and receptor transduction using recombinant human γ-aminobutyric acid type A receptors. Mol Pharmacol 52:1150–1156PubMedGoogle Scholar
  67. Ernst M, Brauchart D, Boresch S, Sieghart W (2003) Comparative modeling of GABAA receptors: limits, insights, future developments. Neuroscience 119:933–943PubMedGoogle Scholar
  68. Farrant M, Nusser Z (2005) Variations on an inhibitory them: phasic and tonic activation of GABAA receptors. Nat Rev 6:215–229Google Scholar
  69. Feng HJ, Kang JQ, Song L, Dibbens L, Mulley J, Macdonald RL (2006) δ subunit susceptibility variants E177A R220H associated with complex epilepsy alter channel gating and surface expression of α4β2δ GABAA receptors. J Neurosci 26:1499–1506PubMedGoogle Scholar
  70. Fleming RL, Acheson SK, Moore SD, Wilson WA, Swartzwelder HS (2011) GABA transport modulates the ethanol sensitivity of tonic inhibition in the rat dentate gyrus. Alcohol 45:577–583PubMedGoogle Scholar
  71. Freiss E, Schiffelholz T, Steckler T, Steiger A (2000) Dehydroepiandorsterone—a neurosteroid. Eur J Clin Invest Suppl 3:46–50Google Scholar
  72. Frye CA (1995) The neuroactive steroid 3α,5α-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy. Brain Res 696:113–120PubMedGoogle Scholar
  73. Galanopoulou AS (2008a) Dissociated gender-specific effects of recurrent seizures on GABA signaling in CA1 pyramidal neurons: role of GABAA receptors. J Neurosci 28:1557–1567PubMedGoogle Scholar
  74. Galanopoulou AS (2008b) GABAA receptors in normal development and seizures: friends or foes. Curr Neuropharmacol 6:1–20PubMedGoogle Scholar
  75. Gangisetty O, Reddy DS (2009) The optimization of TaqMan real-time RT-PCR assay for transcriptional profiling of GABAA receptor subunit plasticity. J Neurosci Methods 181:58–66PubMedGoogle Scholar
  76. Gangisetty O, Reddy DS (2010) Neurosteroid withdrawal regulates GABAA receptor α4-subunit expression and seizure susceptibility by activation of progesterone receptor-independent early growth response factor-3 pathway. Neuroscience 170:865–880PubMedGoogle Scholar
  77. Gartside SE, Griffith NC, Kaura V, Ingram CD (2010) The neurosteroid dehydroepiandrosterone (DHEA) and its metabolites alter 5-HT neuronal activity via modulation of GABAA receptors. J Psychopharmacol 24:1717–1724PubMedGoogle Scholar
  78. Gee KW, Bolger MB, Brinton RE, Coirini H, McEwen BS (1988) Steroid modulation of the chloride ionophore in rat brain: structure–activity requirements, regional dependence and mechanism of action. J Pharmacol Exp Ther 246:803–812PubMedGoogle Scholar
  79. Gibbs JW 3rd, Shumate MD, Coulter DA (1997) Differential epilepsy-associated alterations in postsynaptic GABAA receptor function in dentate granule and CA1 neurons. J Physiol 77:1924–1938Google Scholar
  80. Gibson CJ, Meyer RC, Hamm RJ (2010) Traumatic brain injury and the effects of diazepam, diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus. J Biomed Sci 17:38PubMedGoogle Scholar
  81. Glykys J, Mann EO, Mody I (2008) Which GABAA receptor subunits are necessary for tonic inhibition in the hippocampus? J Neurosci 28:1421–1426PubMedGoogle Scholar
  82. Glykys J, Mody I (2007) Activation of GABAA receptors: views from outside the synaptic cleft. Neuron 56:763–770PubMedGoogle Scholar
  83. Glykys J, Peng Z, Chandra D, Homanics GE, Houser CR, Mody I (2007) A new naturally occurring GABAA receptor subunit with high sensitivity to ethanol. Nat Neurosci 10:40–48PubMedGoogle Scholar
  84. Goodkin HP, Yeh JL, Kapur J (2005) Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci 25:5511–5520PubMedGoogle Scholar
  85. Gulinello M, Smith SS (2003) Anxiogenic effects of neurosteroid exposure: sex differences and altered GABAA receptor pharmacology in adult rats. J Pharm Exp Ther 305:541–548Google Scholar
  86. Hadley SH, Amin J (2007) Rat α6β2δ GABAA receptors exhibit two distinct and separable agonist affinities. J Physiol 581:1001–1018PubMedGoogle Scholar
  87. Hajos N, Nusser Z, Rancz EA, Freund TF, Mody I (2000) Cell type- and synapse-specific variability in synaptic GABAA receptor occupancy. Eur J Neurosci 12:810–818PubMedGoogle Scholar
  88. Hamann M, Rossi DJ, Attwell D (2002) Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex. Neuron 33:625–633PubMedGoogle Scholar
  89. Han JW, Nakamura M, Choi IS, Cho JH, Park HM, Lee MG, Choi BJ, Jang HJ, Jang IS (2009) Differential pharmacological properties of GABAA receptors in axon terminals and soma of dentate gyrus granule cells. J Neurochem 109:995–1007PubMedGoogle Scholar
  90. Hancar HJ, Chutsrinopkun P, Meera P, Supavilai P, Sieghart W, Wallner M, Olsen RW (2006) Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to α4/6β3δ GABAA receptors. Proc Natl Acad Sci U S A 103:8546–8551Google Scholar
  91. Harney SC, Frenquelli BG, Lambert JJ (2003) Phosphorylation influences neurosteroid modulation of synaptic GABAA receptors in rat CA1 and dentate gyrus neurones. Neuropharmacology 45:873–883PubMedGoogle Scholar
  92. Harrison NL, Simmonds MA (1984) Modulation of the GABA receptor complex by a steroid anaesthetic. Brain Res 323:287–292PubMedGoogle Scholar
  93. Harrison NL, Vicini S, Barker JL (1987) A steroid anesthetic prolongs inhibitory postsynaptic currents in cultured rat hippocampal neurons. J Neurosci 7:604–609Google Scholar
  94. He J, Hoffman SW, Stein DG (2004) Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain injury. Restor Neurol Neurosci 22:19–31PubMedGoogle Scholar
  95. Heinemann U, Beck H, Dreier JP, Ficker E, Stabel J, Zhang CL (1992) The dentate gyrus as a regulated gate for the propagation of epileptiform activity. Epilepsy Res 7(Suppl):273–280Google Scholar
  96. Herd MB, Belelli LJJ (2007) Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors. Pharamcol Ther 116:20–34Google Scholar
  97. Herd MB, Haythornwaite AR, Rosahl TW, Wafford KA, Homanics GE, Lambert JJ, Belelli D (2008) The expression of GABAA β subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells. J Physiol 586:989–1004PubMedGoogle Scholar
  98. Herzog AG (1999) Psychoneuroendocrine aspects of temporolimbic epilepsy: part II: epilepsy and reproductive steroids. Psychosomatics 40:102–108PubMedGoogle Scholar
  99. Herzog AG (2009) Hormonal therapies: progesterone. Neurotherapeutics 6:383–391PubMedGoogle Scholar
  100. Holter NI, Zylla MM, Zuber N, Bruehl C, Draguhn A (2010) Tonic GABAergic control of mouse dentate granule cells during postnatal development. Eur J Neurosci 32:1300–1309PubMedGoogle Scholar
  101. Horak M, Vlcek K, Petrovic M, Chodounska H, Vyklicky L Jr (2004) Molecular mechanism of pregnenolone sulfate action at NR1/NR2B receptors. J Neurosci 24:10318–10325PubMedGoogle Scholar
  102. Hosie AM, Clarke L, da Silva H, Smart TG (2009) Conserved site for neurosteroid modulation of GABAA receptors. Neuropharmacology 56:149–154PubMedGoogle Scholar
  103. Hosie AM, Dunne EL, Harvey RJ, Smart TG (2003) Zinc-mediated inhibition of GABAA receptors: discrete binding sites underlie subtype specificity. Nat Neurosci 6:362–369PubMedGoogle Scholar
  104. Hosie AM, Wilkins ME, da Silva HMA, Smart TG (2006) Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nat Lett 444:486–489Google Scholar
  105. Hosie AM, Wilkins ME, Smart TG (2007) Neurosteroid binding sites on GABAA receptors. Pharmacol Ther 116:7–19PubMedGoogle Scholar
  106. Houser CR, Esclapez M (2003) Downregulation of the α5 subunit of the GABAA receptor in the pilocarpine model of temporal lobe epilepsy. Hippocampus 13:633–645PubMedGoogle Scholar
  107. Houston CM, McGee TP, Mackenzie G, Troyano-Cuturi K, Rodriguez PM, Kutsarova E, Diamanti E, Hosie AM, Franks NP, Brickley SG (2012) Are extrasynaptic GABAA receptors important targets for sedative/hypnotic drugs? J Neurosci 32:3887–3897PubMedGoogle Scholar
  108. Hsu FC, Smith SS (2003) Progesterone withdrawal reduces paired-pulse inhibition in rat hippocampus: dependence on GABAA receptor α4 subunit upregulation. J Neurophysiol 89:186–198PubMedGoogle Scholar
  109. Hsu FC, Waldeck R, Faber DS, Smith SS (2003) Neurosteroid effects on GABAergic synaptic plasticity in hippocampus. J Neurophysiol 89:1929–1940PubMedGoogle Scholar
  110. Ing T, Poulter MO (2007) Diversity of GABAA receptor synaptic currents on individual pyramidal cortical neurons. Eur J Neurosci 25:723–734PubMedGoogle Scholar
  111. Iwakiri M, Mizukami K, Ishikawa M, Asada T (2006) GABAA receptor γ subunits in the hippocampus of the rat after perforant pathway lesion. Neurosci Lett 394:88–91PubMedGoogle Scholar
  112. Jacob TC, Moss SJ, Jurd R (2008) GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci 9:331–343PubMedGoogle Scholar
  113. Jia F, Yue M, Chandra D, Keramidas A, Goldstein PA, Homanics GE, Harrison NL (2008) Taurine is a potent activator of extrasynaptic GABAA receptors in the thalamus. J Neurosci 28:106–115PubMedGoogle Scholar
  114. Jefcoate C (2002) High-flux mitochondrial cholesterol trafficking, a specialized function of the adrenal cortex. J Clin Invest 110:881–890PubMedGoogle Scholar
  115. Jursky F, Fuchs K, Buhr A, Tretter V, Sigel E, Sieghart W (2000) Identification of amino acid residues of GABAA receptor subunits contributing to the formation and activity of the tert-butylbicyclophosphorothionate binding site. J Neurochem 74:1310–1316PubMedGoogle Scholar
  116. Kaminski RM, Fu Z, Venkatesan K, Mazzuferi M, Leclerq K, Seutin V, Vicini S (2011) 11-Deoxycortisol impedes GABAergic neurotransmission and induces drug-resistant status epilepticus in mice. Neuropharmacology 60:1098–1108PubMedGoogle Scholar
  117. Kaminski RM, Marini H, Kim WJ, Rogawski MA (2005) Anticonvulsant activity of androsterone and etiocholanolone. Epilepsia 46:819–827PubMedGoogle Scholar
  118. Kaminski RM, Marini H, Ortinski PI, Vicini S, Rogawski MA (2006) The pheromone androstenol (5α-androst-16-en-3α-ol) is a neurosteroid positive modulator of GABAA receptors. J Pharmacol Exp Ther 317:694–703PubMedGoogle Scholar
  119. Katona BW, Krishnan K, Cai ZY, Manion BD, Benz A, Taylor A, Evers AS, Zorumski CF, Mennerick S, Covey DF (2008) Neurosteroid analogues. 12. Potent enhancement of GABA-mediated chloride currents GABAA receptors by ent-androgens. Eur J Med Chem 43:107–113Google Scholar
  120. Kaur KH, Baur R, Sigel E (2009) Unanticipated structural and functional properties of δ-subunit-containing GABAA receptors. J Biol Chem 284:7889–7896PubMedGoogle Scholar
  121. Kelley MH, Kuroiwa M, Taguchi N, Herson PS (2011) Sex difference in sensitivity to allopregnanolone neuroprotection in mice correlates with effect on spontaneous inhibitory post synaptic currents. Neuropharmacology 61:724–729PubMedGoogle Scholar
  122. Kelley SP, Alan JK, O’Buckley TK, Mennerick S, Krishnan K, Covey DF, Morrow AL (2007) Antagonism of neurosteroid modulation of native gamma-aminobutyric acid receptors by (3α,5α)-17-phenylandrost-16-en-3-ol. Eur J Pharmacol 572:94–101PubMedGoogle Scholar
  123. Khanna M, Qin KN, Cheng KC (1995) Distribution of 3α-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans. J Steroid Biochem Mol Biol 53:41–46PubMedGoogle Scholar
  124. Kharlamov EA, Lepsveridze E, Meparishvili M, Solomonia RO, Lu B, Miller ER, Kelly KM, Mtchedlishvili Z (2011) Alterations of GABAA and glutamate receptor subunits and heat shock protein in rat hippocampus following traumatic brain injury and in posttraumatic epilepsy. Epilepsy Res 95:20–34PubMedGoogle Scholar
  125. Kia A, Ribiero F, Nelson R, Gavriolovici C, Ferguson SSG, Poulter MO (2011) Kindling alters neurosteroid-induced modulation of phasic and tonic GABAA receptor-mediated currents: role of phosphorylation. J Neurochem 116:1043–1056PubMedGoogle Scholar
  126. Kim BG, Cho JH, Choi IS, Lee MG, Jang IS (2011) Modulation of presynaptic GABAA receptors by endogenous neurosteroids. Br J Pharmacol 164:1698–1710PubMedGoogle Scholar
  127. Kita A, Furukawa K (2008) Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice. Pharmacol Biochem Behav 89:171–178PubMedGoogle Scholar
  128. Knoflach F, Dietmar B, Wang Y, Scheurer L, Luddens H, Hamilton BJ, Carter DB, Mohler H, Benson JA (1996) Pharmacological modulation of the diazepam-insensitive recombinant γ-aminobutyric acidA receptors α4β2γ2 and α6β2γ2. Mol Pharmacol 50:1253–1261PubMedGoogle Scholar
  129. Kokate TG, Cohen AL, Karp E, Rogawski MA (1996) Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice. Neuropharmacology 35:1049–1056Google Scholar
  130. Kokate TG, Juhng KN, Kirkby RD, Llamas J, Yamaguchi S, Rogawski MA (1999) Convulsant actions of the neuroactive steroid pregnenolone sulfate in mice. Brain Res 831:119–124PubMedGoogle Scholar
  131. Kokate TG, Svensson BE, Rogawski MA (1994) Anticonvulsant activity of neurosteroids: correlation with γ-aminobutyric acid-evoked chloride current potentiation. J Pharmacol Exp Ther 270:1223–1229PubMedGoogle Scholar
  132. Kokate TG, Yamaguchi S, Pannell LK, Rajamani U, Carroll DM, Grossman AB, Rogawski MA (1998) Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice. J Pharmacol Exp Ther 287:553–558PubMedGoogle Scholar
  133. Korneyev A, Pan BS, Polo A, Romeo E, Guidotti A, Costa E (1993) Stimulation of brain pregnenolone synthesis by mitochondrial diazepam binding inhibitor receptor ligands in vivo. J Neurochem 61:1515–1524PubMedGoogle Scholar
  134. Korpi ER, Kuner T, Seeburg PH, Lüddens H (1995) Selective antagonist for the cerebellar granule cell-specific gamma-aminobutyric acid type A receptor. Mol Pharmacol 47:283–289PubMedGoogle Scholar
  135. Korpi ER, Lüddens H (1997) Furosemide interaction with brain GABAA receptors. Br J Pharmacol 120:741–748PubMedGoogle Scholar
  136. Korpi ER, Mihalek RM, Sinkkonen ST, Hauer B, Hevers W, Homanics GE, Sieghart W, Lüddens H (2002) Altered receptor subtypes in the forebrain of GABAA receptor δ subunit-deficient mice: recruitment of γ2 subunits. Neuroscience 109:733–743PubMedGoogle Scholar
  137. Kralic JE, Sidler C, Parpan F, Homanics GE, Morrow AL, Fritschy JM (2006) Compensatory alteration of inhibitory synaptic current in cerebellum and thalamus of γ-aminobutyric acid type A receptor α1 subunit knockout mice. J Comp Neurol 495:408–421PubMedGoogle Scholar
  138. Kristensen AS, Andersen J, Jorgensen TN, Sorensen L, Eriksen J, Lol CJ, Stromgaard K, Gether U (2011) SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev 63:585–640PubMedGoogle Scholar
  139. Kulkarni SK, Reddy DS (1995) Neuroactive steroids: a new class of neuromodulators. Drugs Today 31:433–455Google Scholar
  140. Kuver A, Shen H, Smith SS (2012) Regulation of the surface expression of α4β2δ GABAA receptors by high efficacy states. Brain Res 1463:1–20PubMedGoogle Scholar
  141. Lagrange AH, Botzolakis EJ, Macdonald RL (2007) Enhanced macroscopic desensitization shapes the response of α4 subtype-containing GABAA receptors to synaptic and extrasynaptic GABA. J Physiol 578:655–676PubMedGoogle Scholar
  142. Lambert JJ, Belelli D, Hill-Venning C, Peters JA (1995) Neuroactive steroids and GABAA receptor function. Trends Pharmacol Sci 16:295–303PubMedGoogle Scholar
  143. Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA (2003) Neurosteroid modulation of GABAA receptors. Prog Neurobiol 71:67–80PubMedGoogle Scholar
  144. Lambert JJ, Cooper MA, Simmons RDJ, Weir CJ, Belelli D (2009) Neurosteroids: endogenous allosteric modulators of GABAA receptors. Psychoneuroendocrinology 34S:S48–S58Google Scholar
  145. Lan NC, Gee KW, Bolger MB, Chen JS (1991) Differential responses of expressed recombinant human γ-aminobutyric acidA receptors to neurosteroids. J Neurochem 57:1818–1821PubMedGoogle Scholar
  146. Laurie DJ, Wisden W, Seeburg PH (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci 12:4151–4172PubMedGoogle Scholar
  147. Lavoie AM, Tingey JJ, Harrison NL, Pritchett DB, Twyman RE (1997) Activation and deactivation rates of recombinant GABAA receptor channels are dependent on α-subunit isoform. Biophys J 73:2518–2526PubMedGoogle Scholar
  148. Lawrence C, Martin BS, Sun C, Williamson J, Kapur J (2010) Endogenous neurosteroid synthesis modulates seizure frequency. Ann Neurol 67:689–693PubMedGoogle Scholar
  149. Lee S, Yoon BE, Berglund K, Oh SJ, Park H, Shin HS, Augustine GJ, Lee CJ (2010) Channel-mediated tonic GABA release from glia. Science 330:790–796PubMedGoogle Scholar
  150. Leil TA, Chen ZW, Chang CS, Olsen RW (2004) GABAA receptor-associated protein traffics GABAA receptors to the plasma membrane in neurons. J Neurosci 24:11429–11438PubMedGoogle Scholar
  151. Lerma J, Herranz AS, Herreras O, Abraira V, Martín del Río R (1986) In vivo determination of extracellular concentration of amino acids in the rat hippocampus. A method based on brain dialysis and computerized analysis. Brain Res 384:145–155PubMedGoogle Scholar
  152. Li GD, Chiara DC, Cohen JB, Olsen RW (2009) Neurosteroids allosterically modulate binding of the anesthetic etomidate to γ-aminobutyric acid type A receptors. J Biol Chem 284:11771–11775PubMedGoogle Scholar
  153. Liang J, Suryanarayanan A, Chandra D, Homanics GE, Olsen RW, Spigelman I (2008) Functional consequences of GABAA receptor α4 subunit deletion on synaptic and extrasynaptic currents in mouse dentate granule cells. Alcohol Clin Exp Res 32:19–26PubMedGoogle Scholar
  154. Lothman EW, Stringer JL, Bertram EH (1992) The dentate gyrus as a control point for seizures in the hippocampus and beyond. Epilepsy Res Suppl 7:301–313PubMedGoogle Scholar
  155. Luscher B, Fuchs T, Kilpatrick CL (2011) GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron 70:385–409PubMedGoogle Scholar
  156. Luscher B, Keller CA (2004) Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol Ther 102:195–221PubMedGoogle Scholar
  157. Madsen KK, Ebert B, Clausen RP, Povl K-L, Schousboe A, White HS (2011) Selective GABA reuptake inhibitors tiagabine and EF1502 exhibit mechanistic differences to modulate the ataxia and anticonvulsant action of the extrasynaptic GABAA receptor agonist gaboxadol. J Pharm Exp Ther 338:214–219Google Scholar
  158. Maguire J, Ferando I, Simonsen C, Mody I (2009) Excitability changes related to GABAA receptor plasticity during pregnancy. J Neurosci 29:9592–9601PubMedGoogle Scholar
  159. Maguire J, Mody I (2007) Neurosteroid synthesis-mediated regulation of GABAA receptors: relevance to ovarian cycle and stress. J Neurosci 27:2155–2162PubMedGoogle Scholar
  160. Maguire J, Mody I (2008) GABAAR plasticity during pregnancy: relevance to postpartum depression. Neuron 59:207–213PubMedGoogle Scholar
  161. Maguire JL, Stell BM, Rafizadeh M, Mody I (2005) Ovarian cycle-linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 8:797–804PubMedGoogle Scholar
  162. Maitra R, Reynolds JN (1999) Subunit dependent modulation of GABAA receptor function by neuroactive steroids. Brain Res 819:75–82PubMedGoogle Scholar
  163. Majewska MD (1992) Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 38:379–395Google Scholar
  164. Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986) Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232(4753):1004–1007PubMedGoogle Scholar
  165. Mangan PS, Sun C, Carpenter M, Goodkin HP, Sieghart W, Kapur J (2005) Cultured hippocampal pyramidal neurons express two kinds of GABAA receptors. Mol Pharmacol 67:775–788PubMedGoogle Scholar
  166. McCartney MR, Deeb TZ, Henderson TN, Hales TG (2007) Tonically active GABAA receptors in hippocampal pyramidal neurons exhibit constitutive GABA-independent gating. Mol Pharmacol 71:539–548PubMedGoogle Scholar
  167. Meera P, Olsen RW, Otis TS, Wallner M (2009) Etomidate, propofol and the neurosteroid THDOC increase the GABA efficacy of recombinant α4β3δ and α4β3 GABAA receptors expressed in HEK cells. Neuropharmacology 56:155–160PubMedGoogle Scholar
  168. Meera P, Wallner M, Otis TS (2011) Molecular basis for the high THIP/gaboxadol sensitivity of extrasynaptic GABAA receptors. J Neurophysiol 106:2057–2064PubMedGoogle Scholar
  169. Melcangi RC, Poletti A, Cavarretta I, Celotti F, Colciago A, Magnaghi V, Motta M, Negri-Cesi P, Martini L (1998) The 5α-reductase in the central nervous system: expression and modes of control. J Steroid Biochem Mol Biol 65:295–299PubMedGoogle Scholar
  170. Mennerick S, He Y, Jiang X, Manion BD, Wang M, Shute A, Benz A, Evers AS, Covey DF, Zorumski CF (2004) Selective antagonism of 5α-reduced neurosteroid effects at GABAA receptors. Mol Pharmacol 65:1191–1197PubMedGoogle Scholar
  171. Midzak A, Akula N, Lecanu L, Papadopoulos V (2011a) Novel androstanediol interacts with the mitochondrial translocator protein and controls steroidogenesis. J Biol Chem 286:9875–9887PubMedGoogle Scholar
  172. Midzak A, Rone M, Aghazadeh Y, Culty M, Papdopoulos V (2011b) Mitochondrial protein import and the steroidogenic mitochondria. Mol Cell Endocrinol 336:70–79PubMedGoogle Scholar
  173. Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi Z, Lagenaur C, Tretter V, Sieghart W, Anagnostaras SG et al (1999) Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci U S A 96:12905–12910PubMedGoogle Scholar
  174. Mitchell EA, Gentet LJ, Dempster J, Belelli D (2007) GABAA and glycine receptor-mediated transmission in rat lamina II neurones: relevance to the analgesic actions of neuroactive steroids. J Physiol 583:1021–1040PubMedGoogle Scholar
  175. Mitchell EA, Herd MB, Gunn BG, Lambert JJ, Belelli D (2008) Neurosteroid modulation of GABAA receptors: molecular determinants and significance in health and disease. Neurochem Int 52:588–595PubMedGoogle Scholar
  176. Mitchell SJ, Silver RA (2003) Shunting inhibition modulates neuronal gain during synaptic excitation. Neuron 38:433–445PubMedGoogle Scholar
  177. Mitev YA, Darwish M, Wolf SS, Holsboer F, Almedia OFX, Patchev VK (2003) Gender differences in the regulation of 3α-hydroxysteroid dehydrogenase in rat brain and sensitivity to neurosteroid-mediated stress protection. Neuroscience 120:541–549PubMedGoogle Scholar
  178. Mody I (2001) Distinguishing between GABAA receptors responsible for tonic and phasic conductances. Neurochem Res 26:907–913PubMedGoogle Scholar
  179. Mody I (2012) Plasticity of GABAA receptors relevant to neurosteroid actions. Jasper’s basic mechanisms of the epilepsies, 4th edn. NCBI, BethesdaGoogle Scholar
  180. Mohler H, Fritschy JM, Rudolph U (2002) A new benzodiazepine pharmacology. J Pharmacol Exp Ther 300:2–8PubMedGoogle Scholar
  181. Mortensen M, Ebert B, Wafford K, Smart TG (2010) Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors. J Physiol 588:1251–1268PubMedGoogle Scholar
  182. Mortensen M, Patel B, Smart TG (2012) GABA potency at GABAA receptors found in synaptic and extrasynaptic zones. Front Neurosci 6:1–10Google Scholar
  183. Mortensen M, Smart TG (2010) Extrasynaptic αβ subunit GABAA receptors on rat hippocampal pyramidal neurons. J Physiol 577:841–856Google Scholar
  184. Mostallino MC, Mura ML, Maciocco E, Murru L, Sanna E, Biggio G (2006) Changes in expression of the δ subunit of the GABAA receptor and in receptor function induced by progesterone exposure and withdrawal. J Neurochem 99:321–332PubMedGoogle Scholar
  185. Mtchedlishvili Z, Lepsveridze E, Xu H, Kharlamov EA, Lu B, Kelly KM (2010) Increase of GABAA receptor-mediated tonic inhibition in dentate granule cells after traumatic brain injury. Neurobiol Dis 38:464–475PubMedGoogle Scholar
  186. Mtchedlishvili Z, Kapur J (2003) A presynaptic action of the neurosteroid pregnenolone sulfate on GABAergic synaptic transmission. Mol Pharmacol 64:857–864Google Scholar
  187. Mtchedlishvili Z, Sun CS, Harrison MB, Kapur J (2003) Increased neurosteroid sensitivity of hippocampal GABAA receptors during postnatal development. Neuroscience 118:655–666PubMedGoogle Scholar
  188. Mukherjee J, Kretschmannova K, Gouzer G, Maric HM, Ramsden S, Tretter V, Harvey K, Davies PA, Triller A, Schindelin H et al (2011) The residence time of GABAARs at inhibitory synapses is determined by direct binding of the receptor α1 subunit to gephyrin. J Neurosci 31:14677–14687PubMedGoogle Scholar
  189. Nagaya N, Macdonald RL (2001) Two γ2L subunit domains confer low Zn2+ sensitivity to ternary GABAA receptors. J Physiol 532:17–30PubMedGoogle Scholar
  190. Nohria V, Tsai J, Shaw K, Rogawski MA, Pieribone VA, Farfel G (2010) Ganaxolone, in Bialer M, et al., Progress report on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT X). Epilepsy Res 92:104–107Google Scholar
  191. Nothdurfter C, Rammes G, Baghai TC, Schüle C, Schumacher M, Papadopoulos V, Rupprecht R (2012) TSPO (18 kDa) as a target for novel anxiolytics with a favourable side-effect profile. J Neuroendocrinol 24(1):82–92PubMedGoogle Scholar
  192. Nusser Z, Mody I (2002) Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J Neurophysiol 87:2624–2628PubMedGoogle Scholar
  193. Nuñez JL, McCarthy MM (2007) Evidence for an extended duration of GABA-mediated excitation during the developing male versus female hippocampus. Dev Neurobiol 67:1879–1890PubMedGoogle Scholar
  194. Olsen RW, Sieghart W (2009) GABAA receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 56:141–148PubMedGoogle Scholar
  195. Ortinski PI, Lu C, Takagagi K, Fu Z, Vicini S (2004) Expression of distinct α subunits of GABAA receptor regulates inhibitory synaptic strength. J Neurophysiol 92:1718–1727PubMedGoogle Scholar
  196. Otis TS, Koninck YD, Mody I (1994) Lasting potentiation of inhibition is associated with an increased number of γ-aminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents. Proc Natl Acad Sci U S A 91:7698–7702PubMedGoogle Scholar
  197. Pandit S, Jeong JA, Jo JY, Cho HS, Kim DW, Kim JM, Ryu PD, Lee SY, Kim HW, Jeon BH, Park JB (2013) Dual mechanisms diminishing tonic GABAA inhibition of dentate gyrus granule cells in Noda epileptic rats. J Neurophysiol 110:95–102PubMedGoogle Scholar
  198. Paoletti AM, Romagnino S, Contu R, Orru MM, Marotto MF, Zedda P, Lello S, Biggio G, Concas A, Melis GB (2006) Observational study on the stability of the psychological status during normal pregnancy and increased blood levels of neuroactive steroids with GABAA receptor agonist activity. Psychoneuroendocrinology 31:485–492PubMedGoogle Scholar
  199. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère J, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang M et al (2006) Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27:402–409PubMedGoogle Scholar
  200. Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB J 6:2311–2322PubMedGoogle Scholar
  201. Pavlov I, Huusko N, Drexel M, Kirchmair E, Sperk G, Pitkanen A, Walker MC (2011) Progressive loss of phasic, but not tonic, GABAA receptor-mediated inhibition in dentate granule cells in a model of post-traumatic epilepsy in rats. Neuroscience 194:208–219PubMedGoogle Scholar
  202. Peng Z, Hauer B, Mihalek RM, Homanics GE, Sieghart W, Olsen RW, Houser CR (2002) GABAA receptor changes in δ subunit-deficient mice: altered expression of α4 and γ2 subunits in the forebrain. J Comp Neurol 446:179–197PubMedGoogle Scholar
  203. Peng Z, Huang CS, Stell BM, Mody I, Houser CR (2004) Altered expression of the δ subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J Neurosci 24:8629–8639PubMedGoogle Scholar
  204. Persohn E, Malherbe P, Richard JG (1992) Comparative molecular neuroanatomy of cloned GABAA receptor subunits in the rat CNS. J Comp Neurol 326:193–216PubMedGoogle Scholar
  205. Petratos S, Hirst JJ, Mendis S, Anikijenko P, Walker DW (2000) Localization of p450scc and 5α-reductase type-2 in the cerebellum of fetal and newborn sheep. Dev Brain Res 123:81–86Google Scholar
  206. Petrovic M, Sedlacek M, Cais O, Horak M, Chodounska H, Vyklicky L Jr (2009) Pregnenolone sulfate modulation of N-methyl-D-aspartate receptors is phosphorylation dependent. Neuroscience 160:616–628PubMedGoogle Scholar
  207. Pillai GV, Smith AJ, Hunt PA, Simpson PB (2004) Multiple structural features of steroids mediate subtype-selective effects on human α4β3δ GABAA receptors. Biochem Pharmacol 68:819–831PubMedGoogle Scholar
  208. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000) GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101:815–850PubMedGoogle Scholar
  209. Porcu P, O’Buckley TK, Alward SE, Marx CE, Shampine LJ, Girdler SS, Morrow AL (2009) Simultaneous quantification of GABAergic 3α,5α/3α,5β neuroactive steroids in human and rat serum. Steroids 74:463–473PubMedGoogle Scholar
  210. Prenosil GA, Schneider Gasser EM, Rudolph U, Keist R, Fritschy JM, Vogt KE (2006) Specific subtypes of GABAA receptors mediate phasic and tonic forms of inhibition in hippocampal pyramidal neurons. J Neurophysiol 96:846–857PubMedGoogle Scholar
  211. Prince RJ, Simmonds MA (1992) 5 beta-pregnan-3 beta-ol-20-one, a specific antagonist at the neurosteroid site of the GABAA receptor-complex. Neurosci Lett 135:273–275PubMedGoogle Scholar
  212. Puia G, Ducic I, Vicini S, Costa E (1993) Does neurosteroid modulatory efficacy depend on GABAA receptor subunit composition? Receptors Channels 1:135–142PubMedGoogle Scholar
  213. Puia G, Santi M, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E (1990) Neuroactive steroids act on recombinant human GABAA receptors. Neuron 4:759–765PubMedGoogle Scholar
  214. Purdy RH, Morrow AL, Blinn JR, Paul SM (1990) Synthesis, metabolism, and pharmacological activity of 3α-hydroxy steroids which potentiate GABA-receptor-mediated chloride ion uptake in rat cerebral cortical synaptoneurosomes. J Med Chem 33:1572–1581PubMedGoogle Scholar
  215. Purdy RH, Morrow AL, Moore PH Jr, Paul SM (1991) Stress-induced elevations of γ-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci U S A 88:4553–4557PubMedGoogle Scholar
  216. Quirk K, Blurton P, Fletcher S, Leeson P, Tang F, Mellilo D, Ragan CI, McKernan RM (1996) [3H]L-655,708, a novel ligand selective for the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit. Neuropharmacology 35:1331–1335PubMedGoogle Scholar
  217. Rajasekaran K, Joshi S, Sun C, Mtchhedlishvilli Z, Kapur J (2010) Receptors with low affinity for neurosteroids and GABA contribute to tonic inhibition of granule cells in epileptic animals. Neurobiol Dis 40:490–501PubMedGoogle Scholar
  218. Ramakrishnan L, Hess GP (2010) Mechanism of potentiation of a dysfunctional epilepsy-linked mutated GABAA receptor by a neurosteroid (3α,21-dihydroxy-5α-pregnan-20-one): transient kinetic investigations. Biochemistry 49:7892–7901PubMedGoogle Scholar
  219. Ransom CB, Wu Y, Richerson GB (2010) Postdepolarization potentiation of GABAA receptors: a novel mechanism regulating tonic conductance in hippocampal neurons. J Neurosci 30:7672–7684PubMedGoogle Scholar
  220. Reddy DS (2003a) Pharmacology of endogenous neuroactive steroids. Crit Rev Neurobiol 15:197–234PubMedGoogle Scholar
  221. Reddy DS (2003b) Is there a physiological role for the neurosteroid THDOC in stress-sensitive conditions? Trends Pharmacol Sci 24(3):103–106PubMedGoogle Scholar
  222. Reddy DS (2004a) Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3α-androstanediol and 17β-estradiol. Neuroscience 129:195–207PubMedGoogle Scholar
  223. Reddy DS (2004b) Anticonvulsant activity of the testosterone-derived neurosteroid 3α-androstanediol. Neuroreport 15:515–518PubMedGoogle Scholar
  224. Reddy DS (2006) Physiological role of adrenal deoxycorticosterone-derived neuroactive steroids in stress-sensitive conditions. Neuroscience 138:911–920PubMedGoogle Scholar
  225. Reddy DS (2007) Premenstrual catamenial epilepsy. Womens Health 3:195–206Google Scholar
  226. Reddy DS (2008) Mass spectrometric quantification and physiological–pharmacological activity of androgenic neurosteroids. Neurochem Int 52:541–553PubMedGoogle Scholar
  227. Reddy DS (2009a) The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy. Epilepsy Res 85:1–30PubMedGoogle Scholar
  228. Reddy DS (2009b) Steroid hormones and sex differences in seizure susceptibility. In: Schwartzkroin P (ed) Encyclopedia of basic epilepsy research, vol 1. Academic, Oxford, pp 526–533Google Scholar
  229. Reddy DS (2010) Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res 186:113–137PubMedGoogle Scholar
  230. Reddy DS (2011) Role of anticonvulsant and antiepileptogenic neurosteroids in the pathophysiology and treatment of epilepsy. Front Endocrinol 2(article 38):1–11Google Scholar
  231. Reddy DS (2013a) Neuroendocrine aspects of catamenial epilepsy. Horm Behav 63:254–266PubMedGoogle Scholar
  232. Reddy DS (2013b) Role of hormones and neurosteroids in epileptogenesis. Front Cell Neurosci 7(article 115):1–20Google Scholar
  233. Reddy DS, Apanites LA (2005) Anesthetic effects of progesterone are undiminished in progesterone receptor knockout mice. Brain Res 1033(1):96–101PubMedGoogle Scholar
  234. Reddy DS, Chien B, Ramu K (2005a) A high-performance liquid chromatography-tandem mass spectrometry assay of the androgenic neurosteroid 3α-androstanediol (5α-androstan-3δ,17β-diol) in plasma. Steroids 70:879–885PubMedGoogle Scholar
  235. Reddy DS, O’Malley BW, Rogawski MA (2005b) Anxiolytic activity of progesterone in progesterone receptor knockout mice. Neuropharmacology 48:14–24PubMedGoogle Scholar
  236. Reddy DS, Shetty AK, Apanites LA (2005c) Antiepileptic effects of the neurosteroid allopregnanolone on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy. Epilepsia 46(suppl 8):298Google Scholar
  237. Reddy DS, Carver CM, Clossen BL (2013) Accelerated limbic epileptogenesis in mice lacking delta-subunit extrasynaptic GABA-A receptors. Soc Neurosci Meeting #627.10 (N17)Google Scholar
  238. Reddy DS, Gangisetty O, Briyal S (2010) Disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis. Neuropharmacology 59:573–581PubMedGoogle Scholar
  239. Reddy DS, Gould J, Gangisetty O (2012) A mouse kindling model of perimenstrual catamenial epilepsy. J Pharmacol Exp Ther 341:784–793PubMedGoogle Scholar
  240. Reddy DS, Kuruba R (2013) Experimental models of status epilepticus and neuronal injury for evaluation of therapeutic interventions. International J Mol Sci 14:18284–18318Google Scholar
  241. Reddy DS, Ramanathan G (2012) Finasteride inhibits the disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis. Epilepsy Behav 25(1):92–97Google Scholar
  242. Reddy DS, Jian K (2010) The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors. J Pharmacol Exp Ther 334:1031–1041PubMedGoogle Scholar
  243. Reddy DS, Kulkarni SK (1996) Role of GABAA and mitochondrial diazepam binding inhibitor receptors in the antistress activity of neurosteroids in mice. Psychopharmacology (Berl) 128:280–292Google Scholar
  244. Reddy DS, Kulkarni SK (1997) Differential anxiolytic effects of neurosteroids in the mirrored chamber behavior test in mice. Brain Res 1997(752):61–71Google Scholar
  245. Reddy DS, Kulkarni SK (1998a) The effects of neurosteroids on acquisition and retention of a modified passive-avoidance learning task in mice. Brain Res 791:108–116PubMedGoogle Scholar
  246. Reddy DS, Kulkarni SK (1998b) Proconvulsant effects of neurosteroid pregnenolone sulfate and dehydroepiandrosterone sulfate in mice. Eur J Pharmacol 345:55–59PubMedGoogle Scholar
  247. Reddy DS, Kulkarni SK (1999) Sex and estrous cycle-dependent changes in neurosteroid and benzodiazepine effects on food consumption and plus-maze learning behavior in rats. Pharmacol Biochem Behav 62:53–60PubMedGoogle Scholar
  248. Reddy DS, Kulkarni SK (2000) Development of neurosteroid-based novel psychotropic drugs. Prog Med Chem 37:135–175PubMedGoogle Scholar
  249. Reddy DS, Mohan A (2011) Development and persistence of limbic epileptogenesis are impaired in mice lacking progesterone receptors. J Neurosci 31:650–658PubMedGoogle Scholar
  250. Reddy DS, Rogawski MA (2000a) Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy. J Pharmacol Exp Ther 294:909–915PubMedGoogle Scholar
  251. Reddy DS, Rogawski MA (2000b) Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J Pharmacol Exp Ther 295:1241–1248PubMedGoogle Scholar
  252. Reddy DS, Kim Y-H, Rogawski MA (2001) Neurosteroid withdrawal model of perimenstrual catamenial epilepsy. Epilepsia 42:328–336PubMedGoogle Scholar
  253. Reddy DS, Rogawski MA (2001) Enhanced anticonvulsant activity of neuroactive steroids in a rat model of catamenial epilepsy. Epilepsia 42:337–344PubMedGoogle Scholar
  254. Reddy DS, Rogawski MA (2002) Stress-induced deoxycorticosterone-derived neurosteroids modulate GABAA receptor function and seizure susceptibility. J Neurosci 22:3795–3805PubMedGoogle Scholar
  255. Reddy DS, Rogawski MA (2009) Neurosteroid replacement therapy for catamenial epilepsy. Neurotherapeutics 6:392–401PubMedGoogle Scholar
  256. Reddy DS, Rogawski MA (2010) Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model. Epilepsy Res 89:254–260PubMedGoogle Scholar
  257. Reddy DS, Woodward R (2004) Ganaxolone: a prospective overview. Drugs Future 29:227–242Google Scholar
  258. Reddy DS, Zeng YC (2007) Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor A and B subtypes. Meth Find Exp Clin Pharmacol 29:659–664Google Scholar
  259. Richerson GB, Wu Y (2003) Dynamic equilibrium of neurotransmitter transporters: not just for reuptake anymore. J Neurophysiol 90:1363–1374PubMedGoogle Scholar
  260. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K (1999) The K+/Cl co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251–255PubMedGoogle Scholar
  261. Rossi DJ, Hamann M, Attwell D (2003) Multiple modes of GABAergic inhibition of rat cerebellar granule cells. J Physiol 548:97–110PubMedGoogle Scholar
  262. Rudolph U, Knoflach F (2011) Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nature Rev Drug Discovery 10:685–697Google Scholar
  263. Rudolph U, Mohler H (2004) Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol 44:475–498PubMedGoogle Scholar
  264. Ruiz A, Walker MC, Fabian-Fine R, Kullmann DM (2004) Endogenous zinc inhibits GABAA receptors in a hippocampal pathway. J Neurophysiol 91:1091–1096PubMedGoogle Scholar
  265. Rupprecht R (2003) Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 28:139–168PubMedGoogle Scholar
  266. Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, Groyer G, Adams D, Schumacher M (2010) Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 9:971–988PubMedGoogle Scholar
  267. Rupprecht R, Rammes G, Eser D, Baghai TC, Schüle C, Nothdurfter C, Troxler T, Gentsch C, Kalkman HO, Chaperon F, Uzunov V, McAllister KH, Bertaina-Anglade V, La Rochelle CD, Tuerck D, Floesser A, Kiese B, Schumacher M, Landgraf R, Holsboer F, Kucher K (2009) Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science 325(5939):490–493PubMedGoogle Scholar
  268. Saalmann YB, Kirkcaldie MTK, Waldron S, Calford MB (2007) Cellular distribution of the GABAA receptor-modulating 3α-hydroxy, 5α-reduced pregnane steroids in the adult rat brain. J Neuroendocrinol 19:272–284PubMedGoogle Scholar
  269. Saarelainen KS, Ranna M, Rabe H, Sinkkonen ST, Möykkynen T, Uusi-Oukari M, Linden AM, Lüdens H, Korpi ER (2008) Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic α6β GABAA receptors. J Neurochem 105:338–350PubMedGoogle Scholar
  270. Sancar F, Czajkowski C (2011) Allosteric modulators induce distinct movements at the GABA-binding site interface of the GABAA receptor. Neuropharmacology 60:520–528PubMedGoogle Scholar
  271. Sanna E, Mostallino MC, Murru L, Carta M, Talani G, Zucca S, Mura ML, Maciocco E, Biggio G (2009) Changes in expression and function of extrasynaptic GABAA receptors in the rat hippocampus during pregnancy and after delivery. J Neurosci 29:1755–1765PubMedGoogle Scholar
  272. Santhakumar V, Hanchar HJ, Wallner M, Olsen RW, Otis TS (2006) Contributions of the GABAA receptor α6 subunit to phasic and tonic inhibition revealed by a naturally occurring polymorphism in the α6 gene. J Neurosci 26:3357–3364PubMedGoogle Scholar
  273. Santos VR, De Castro OW, Pun RY, Hester MS, Murphy BL, Loepke AW, Garcia-Cairasco N, Danzer SC (2011) Contributions of mature granule cells to structural plasticity in temporal lobe epilepsy. Neuroscience 197:348–357PubMedGoogle Scholar
  274. Sarkar J, Wakefield S, MacKenzie G, Moss SJ, Maguire J (2011) Neurosteroidogenesis is required for the physiological response to stress: role of neurosteroid-sensitive GABAA receptors. J Neurosci 31:18198–18210PubMedGoogle Scholar
  275. Saxena NC, Macdonald RL (1994) Assembly of GABAA receptor subunits: role of the δ subunit. J Neurosci 14:7077–7086PubMedGoogle Scholar
  276. Saxena NC, Macdonald RL (1996) Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms. Mol Pharmacol 49:567–579PubMedGoogle Scholar
  277. Sayeed I, Stein DG (2009) Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Prog Brain Res 175:219–237PubMedGoogle Scholar
  278. Scimemi A, Semyanov A, Sperk G, Kullman DM, Walker M (2005) Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus. J Neurosci 25:10016–10024PubMedGoogle Scholar
  279. Scholfield CN (1980) Potentiation of inhibition by general anaesthetics in neurones of the olfactory cortex in vitro. Pflugers Arch 383:249–255PubMedGoogle Scholar
  280. Selye H (1941) Anesthetics of steroid hormones. Proc Soc Exp Biol Med 46:116–121Google Scholar
  281. Sedelnikova A, Erkkila BE, Harris H, Zakharkin SO, Weiss DS (2006) Stoichiometry of a pore mutation that abolishes picrotoxin-mediated antagonism of the GABAA receptor. J Physiol 577:569–577PubMedGoogle Scholar
  282. Semyanov A, Walker MC, Kullmann DM, Silver RA (2004) Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci 27:262–269PubMedGoogle Scholar
  283. Serra M, Mostallino MC, Talani G, Pisu MG, Carta M, Mura ML, Floris I, Maciocco E, Sanna E, Biggio G (2006) Social isolation-induced increase in alpha and delta subunit gene expression is associated with a greater efficacy of ethanol on steroidogenesis and GABA receptor function. J Neurochem 98:122–133PubMedGoogle Scholar
  284. Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, Usala L, Purdy RH, Biggio G (2000) Social isolation-induced decreases in both the abundance of neuroactive steroids and GABAA receptor function in rat brain. J Neurochem 75:732–740PubMedGoogle Scholar
  285. Shao LR, Dudek FE (2005) Changes in mIPSCs and sIPSCs after kainite treatment: evidence for loss of inhibitory input to dentate granule cells and possible compensatory responses. J Neurophysiol 94:952–960PubMedGoogle Scholar
  286. Shen H, Gon QH, Yuan M, Smith SS (2005) Short-term steroid treatment increases δ GABAA receptor subunit expression in rat CA1 hippocampus: pharmacological and behavioral effects. Neuropharmacology 49:573–586PubMedGoogle Scholar
  287. Shu HJ, Bracamontes J, Taylor A, Wu K, Eaton MM, Gustav A, Manion B, Evers AS, Krishnan K, Covey DF et al (2012) Characteristics of concatemeric GABAA receptors containing α4/δ subunits expressed in Xenopus oocytes. Br J Pharmacol 165:2228–2243PubMedGoogle Scholar
  288. Shu HJ, Eisenman LN, Jinadasa D, Covey DF, Zorumski CF, Mennerick S (2004) Slow actions of neuroactive steroids at GABAA receptors. J Neurosci 24:6667–6675PubMedGoogle Scholar
  289. Sieghart W (1995) Structure and pharmacology of γ-aminobutyric acidA receptor subtypes. Pharm Rev 47:181–234Google Scholar
  290. Sieghart W (2006) Structure, pharmacology, and function of GABAA receptor subtypes. Adv Pharmacol 54:231–263PubMedGoogle Scholar
  291. Sieghart W, Sperk G (2002) Subunit composition, distribution and function of GABAA receptor subtypes. Curr Top Med Chem 2:795–816PubMedGoogle Scholar
  292. Smith AJ, Alder L, Silk J, Adkins C, Fletcher AE, Scales T, Kerby J, Marshall G, Wafford KA, McKernan RM et al (2001) Effect of α subunit on allosteric modulation of ion channel function in stably expressed human recombinant γ-aminobutyric acidA receptors determined using 36Cl ion flux. Mol Pharmacol 59:1108–1118PubMedGoogle Scholar
  293. Smith SS, Gong QH (2005) Neurosteroid administration and withdrawal alter GABAA receptor kinetics in CA1 hippocampus of female rats. J Physiol 564:421–436PubMedGoogle Scholar
  294. Smith SS, Gong QH, Hsu FC, Markowitz RS, ffrench-Mullen JMH, Li X (1998) GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392:926–929PubMedGoogle Scholar
  295. Smith SS, Shen H, Gong QH, Zhou X (2007) Neurosteroid regulation of GABAA receptors: focus on the α4 and δ subunits. Pharmacol Ther 116:58–76PubMedGoogle Scholar
  296. Snead OC 3rd (1998) Ganaxolone, a selective, high-affinity steroid modulator of the γ-aminobutyric acid-A receptor, exacerbates seizures in animal models of absence. Ann Neurol 44:688–691PubMedGoogle Scholar
  297. Sperk G, Schwarzer C, Tsunashima K, Fuchs K, Sieghart W (1997) GABAA receptor subunits in the rat hippocampus I: immunocytochemical distribution of 13 subunits. Neuroscience 80:987–1000PubMedGoogle Scholar
  298. Spigelman I, Li Z, Banerjee PK, Mihalek RM, Homanics GE, Olsen RW (2002) Behavior and physiology of mice lacking the GABAA receptor δ subunit. Epilepsia 43(suppl 5):3–8PubMedGoogle Scholar
  299. Spigelman I, Li Z, Liang J, Cagetti E, Samzadeh S, Mihalek RM, Homanics GE, Olsen RW (2003) Reduced inhibition and sensitivity to neurosteroids in hippocampus of mice lacking the GABAA receptor δ subunit. J Neurophysiol 90:903–910PubMedGoogle Scholar
  300. Stell BM, Brickley SG, Tang CY, Farrant M, Mody I (2003) Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors. Proc Natl Acad Sci U S A 100:14439–14444PubMedGoogle Scholar
  301. Stell BM, Mody I (2002) Receptors with different affinities mediate phasic and tonic GABAA conductances in hippocampal neurons. J Neurosci 22:RC223PubMedGoogle Scholar
  302. Stoffel-Wagner B (2001) Neuroactive steroid metabolism in the human brain. Eur J Endocrinol 145:669–679PubMedGoogle Scholar
  303. Stoffel-Wagner B, Beyenburg S, Watzka MS, Blumcke I, Bauer J, Schramm J, Bidlingmaier F, Elger CE (2000) Expression of 5α-reductase and 3α-hydroxysteroid oxidoreductase in the hippocampus of patients with chronic temporal lobe epilepsy. Epilepsia 41:140–147PubMedGoogle Scholar
  304. Stoffel-Wagner B, Watzka M, Steckelbroeck S, Ludwig M, Clusmann H, Bidlingmaier F, Casarosa E, Luisi S, Elger CE, Beyenburg S (2003) Allopregnanolone serum levels and expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase isoforms in hippocampal and temporal cortex of patients with epilepsy. Epilepsy Res 54:11–19PubMedGoogle Scholar
  305. Stórustovu S, Ebert B (2003) Gaboxadol: in vitro interaction studies with benzodiazepines and ethanol suggest functional selectivity. Eur J Pharmacol 467:49–56PubMedGoogle Scholar
  306. Stórustovu S, Ebert B (2006) Pharmacological characterization of agonists at δ-containing GABAA receptors: functional selectivity for extrasynaptic receptors is dependent on the absence of γ2. J Pharm Exp Ther 316:1351–1359Google Scholar
  307. Strömberg J, Bäckström T, Lungren P (2005) Rapid non-genomic effects of glucocorticoid metabolites and neurosteroids on the γ-aminobutyric acid-A receptor. Eur J Neurosci 21:2083–2088PubMedGoogle Scholar
  308. Succol F, Fiumelli H, Benfenati F, Cancedda L, Barberis A (2012) Intracellular chloride concentration influences the GABAA receptor subunit composition. Nat Commun 3:738PubMedGoogle Scholar
  309. Sun C, Sieghart W, Kapur J (2004) Distribution of α1, γ2, and δ subunits of GABAA receptors in hippocampal granule cells. Brain Res 1029:207–216PubMedGoogle Scholar
  310. Sun C, Mtchedlishvili Z, Erisir A, Kapur J (2007) Diminished neurosteroid sensitivity of synaptic inhibition and altered location of the α4 subunit of GABAA receptors in an animal model of epilepsy. J Neurosci 27:12641–12650PubMedGoogle Scholar
  311. Sundstrom-Poromaa I, Smith DH, Gong QH, Sabado TN, Li X, Light A, Wiedmann M, Williams K, Smith SS (2002) Hormonally regulated α4β2δ GABAA receptors are a target for alcohol. Nat Neurosci 5:721–722PubMedGoogle Scholar
  312. Suryanarayanan A, Liang J, Meyer EM, Lindemeyer AK, Chandra D, Homanics GE, Sieghart W, Olsen RW, Spigelman I (2011) Subunit compensation and plasticity of synaptic GABAA receptors induced by ethanol in α4 subunit knockout mice. Front Neurosci 5:110PubMedGoogle Scholar
  313. Szyndler J, Maciejak P, Turzynska D, Sobolewska A, Lehner M, Taracha E, Walkowiak J, Skorzewska A, Wislowska-Stanek A, Hamed A et al (2008) Changes in the concentration of amino acids in the hippocampus of pentylenetetrazole-kindled rats. Neurosci Lett 439:245–249PubMedGoogle Scholar
  314. Tang X, Hernandez CC, Macdonald RL (2010) Modulation of spontaneous and GABA-evoked tonic α4β3δ and α4β3γ2L GABAA receptor currents by protein kinase A. J Neurophysiol 103:1007–1019PubMedGoogle Scholar
  315. Tao W, Higgs MH, Spain WJ, Ransom CB (2013) Postsynaptic GABAB receptors enhance GABAA receptor function in dentate gyrus granule cells. J Neurosci 33:3738–3743PubMedGoogle Scholar
  316. Teschemacher A, Kasparov S, Kravitz EA, Rahamimoff R (1997) Presynaptic action of the neurosteroid pregnenolone sulfate on inhibitory transmitter release in cultured hippocampal neurons. Brain Res 772:226–232PubMedGoogle Scholar
  317. Thomas P, Mortensen M, Hosie AM, Smart TG (2005) Dynamic mobility of functional GABAA receptors at inhibitory synapses. Nat Neurosci 8:889–897PubMedGoogle Scholar
  318. Tsuda M, Suzuki T, Misawa M (1997) Modulation of the decrease in the seizure threshold of pentylenetetrazole in diazepam-withdrawn mice by the neuroactive steroid 5α-pregnan-3α,21-diol-20-one (alloTHDOC). Addiction Biol 2:455–460Google Scholar
  319. Tuveri A, Paoletti AM, Orru M, Melis GB, Marotto MF, Zedda P, Marrosu F, Sogliano C, Marra C, Biggio G (2008) Reduced serum level of THDOC, an anticonvulsant steroid, in women with perimenstrual catamenial epilepsy. Epilepsia 49:1221–1229PubMedGoogle Scholar
  320. Twyman RE, Macdonald RL (1992) Neurosteroid regulation of GABAA receptor single-channel kinetic properties of mouse spinal cord neurons in culture. J Physiol 456:215–245PubMedGoogle Scholar
  321. Ueno S, Bracamontes J, Zorumski C, Weiss DS, Steinbach JH (1997) Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor. J Neurosci 17:625–634PubMedGoogle Scholar
  322. Uusi-Oukari M, Korpi ER (2010) Regulation of GABAA receptor subunit expression by pharmacological agents. Pharmacol Rev 62:97–135PubMedGoogle Scholar
  323. Vardya I, Hoestgaard-Jensen K, Nieto-Gonzalez JL, Dósa Z, Boddum K, Holm MM, Wolinsky TD, Jones KA, Dalby NO, Ebert B, Jensen K (2012) Positive modulation of δ-subunit containing GABA(A) receptors in mouse neurons. Neuropharmacology 63:469–479PubMedGoogle Scholar
  324. Vithlani M, Terunuma M, Moss SJ (2011) The dynamic modulation of GABAA receptor trafficking and its role in regulating the plasticity of inhibitory synapses. Physiol Rev 91:1009–1022PubMedGoogle Scholar
  325. Wafford KA, Ebert B (2006) Gaboxadol—a new awakening in sleep. Curr Opin Pharmacol 6:30–36PubMedGoogle Scholar
  326. Wafford KA, Thompson SA, Thomas D, Sikela J, Wilcox AS, Whiting PJ (1996) Functional characterization of human γ-aminobutyric acidA receptors containing the α4 subunit. Mol Pharmacol 50:670–678PubMedGoogle Scholar
  327. Walls AB, Nilsen LH, Eyjolffson EM, Vestergaard HT, Hansen ST, Schousboe A, Sonnewald U, Waagepetersen HS (2010) GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity. J Neurochem 115:1398–1408PubMedGoogle Scholar
  328. Wang M, He Y, Eisenman LN, Fields C, Zeng CM, Mathews J, Benz A, Fu T, Zorumski E, Steinbach JH et al (2002) 3beta-Hydroxypregnane steroids are pregnenolone sulfate-like GABAA receptor antagonists. J Neurosci 22:3366–3375PubMedGoogle Scholar
  329. Wang MD, Rahman M, Zhu D, Johansson IM, Bäckström T (2007) 3β-Hydroxysteroids and pregnenolone sulfate inhibit recombinant rat GABAA receptor through different channel property. Eur J Pharmacol 557:124–131PubMedGoogle Scholar
  330. Wang M, Seippel L, Purdy RH, Bäckström T (1996) Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5alpha-pregnan-20-one. J Clin Endocrinol Metab 81:1076–1082PubMedGoogle Scholar
  331. Wei W, Zhang N, Peng Z, Houser CR, Mody I (2003) Perisynaptic localization of δ subunit-containing GABAA receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci 23:10650–10661PubMedGoogle Scholar
  332. Wieland S, Belluzzi JD, Stein L, Lan NC (1995) Comparative behavioral characterization of the neuroactive steroids 3α-OH, 5α-pregnan-20-one and 3α-OH,5β-pregnan-20-one in rodents. Psychopharmacology (Berl) 118:65–71Google Scholar
  333. Williams CA, Bell SV, Jenkins A (2010) A residue in loop 9 of the β2-subunit stabilizes the closed state of the GABAA receptor. J Biol Chem 285:7281–7287PubMedGoogle Scholar
  334. Williamson J, Mtchedlishvili Z, Kapur J (2004) Characterization of the convulsant action of pregnenolone sulfate. Neuropharmacology 46:856–864PubMedGoogle Scholar
  335. Wilson MA, Biscardi R (1997) Influence of gender and brain region on neurosteroid modulation of GABA responses in rat. Life Sci 60:1679–1691PubMedGoogle Scholar
  336. Wisden W, Herb A, Wieland H, Keinӓnen LH, Seeburg PH (1991) Cloning, pharmacological characteristics and expression pattern of the rat GABAA receptor α4 subunit. FEBS 289:227–230Google Scholar
  337. Wisden W, Laurie DJ, Monyer H, Seeburg PH (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. telencephalon, diencephalon, mesencephalon. J Neurosci 12:1040–1062Google Scholar
  338. Wohlfarth KM, Bianchi MT, Macdonald RL (2002) Enhanced neurosteroid potentiation of ternary GABAA receptors containing the δ subunit. J Neurosci 22:1541–1549PubMedGoogle Scholar
  339. Wojtowicz T, Lebida K, Mozrzymas JW (2008) 17beta-estradiol affects GABAergic transmission in developing hippocampus. Brain Res 1241:7–17Google Scholar
  340. Wu FS, Gibbs TT, Farb DH (1991) Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol Pharmacol 40:333–336PubMedGoogle Scholar
  341. Wu X, Gangisetty O, Carver CM, Reddy DS (2013) Estrous cycle regulation of extrasynaptic δ-containing GABAA receptor-mediated tonic inhibition and limbic epileptogenesis. J Pharmacol Exp Ther 346:146–160PubMedGoogle Scholar
  342. Wu X, Wu Z, Ning G, Guo Y, Ali R, Macdonald RL, De Blas AL, Luscher B, Chen G (2012) GABAA receptor alpha subunits play a direct role in synaptic versus extrasynaptic targeting. J Biol Chem 287:27417–27430PubMedGoogle Scholar
  343. Wu Y, Wang W, Diez-Sampedro A, Richerson GB (2007) Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1. Neuron 56:851–865PubMedGoogle Scholar
  344. Wu Y, Wang W, Richerson GB (2006) The transmembrane sodium gradient influences ambient GABA concentration by altering the equilibrium of GABA transporters. J Neurophysiol 96:2425–2436PubMedGoogle Scholar
  345. Wulff P, Goetz T, Leppӓ E, Linden A-M, Renzi M, Swinny JD, Vekovischeva OY, Sieghart W, Somogyi P, Korpi ER (2007) From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors. Nat Neurosci 10:923–929PubMedGoogle Scholar
  346. Yeung JYT, Canning KJ, Zhu G, Pennefather P, Macdonald JF, Orser BA (2003) Tonically activated GABAA receptors in hippocampal neurons are high-affinity, low-conductance sensors for extracellular GABA. Mol Pharmacol 63:2–8PubMedGoogle Scholar
  347. You H, Dunn SM (2007) Identification of a domain in the δ subunit (S238-V264) of the α4β3δ GABAA receptor that confers high agonist sensitivity. J Neurochem 103:1092–1101PubMedGoogle Scholar
  348. Yu W, Jiang M, Miralles CP, Li RW, Chen G, de Blas AL (2007) Gephyrin clustering is required for the stability of GABAergic synapses. Mol Cell Neurosci 36:484–500PubMedGoogle Scholar
  349. Yu ZY, Wang W, Fritschy JM, Witte OW, Redecker C (2006) Changes in neocortical and hippocampal GABAA receptor subunit distribution during brain maturation and aging. Brain Res 1099:73–81PubMedGoogle Scholar
  350. Zhan RZ, Nadler JV (2009) Enhanced tonic GABA current in normotropic and hilar ectopic dentate granule cells after pilocarpine-induced status epilepticus. J Neurophysiol 102:670–681PubMedGoogle Scholar
  351. Zhang N, Wei W, Mody I, Houser CR (2007) Altered localization of GABAA receptor subunits on dentate granule cell dendrites influence tonic and phasic inhibition in a mouse model of epilepsy. J Neurosci 27:7520–7531PubMedGoogle Scholar
  352. Zheleznova NN, Sedelnikova A, Weiss DS (2008) α1β2δ, a silent GABAA receptor: recruitment by tracazolate and neurosteroids. Br J Pharmacol 153:1062–1071PubMedGoogle Scholar
  353. Zheleznova NN, Sedelnikova A, Weiss DS (2009) Function and modulation of δ-containing GABAA receptors. Psychoneuroendocrinology 34S:S67–S73Google Scholar
  354. Zhu WJ, Vicini S (1997) Neurosteroid prolongs GABAA channel deactivation by altering kinetics of desensitized states. J Neurosci 17:4022–4031Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Neuroscience and Experimental Therapeutics, College of MedicineTexas A&M University Health Science CenterBryanUSA

Personalised recommendations