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Molecular Brain
Published in: Molecular Brain 1/2013

Open Access 01-12-2013 | Research

Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors

Authors: Yajie Sun, Zheng Wu, Shuzhen Kong, Dongyun Jiang, Anar Pitre, Yun Wang, Gong Chen

Published in: Molecular Brain | Issue 1/2013

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Abstract

Background

GABAergic deficit is one of the major mechanisms underlying epileptic seizures. Previous studies have mainly focused on alterations of synaptic GABAergic inhibition during epileptogenesis. Recent work suggested that tonic inhibition may also play a role in regulating epileptogenesis, but the underlying mechanism is not well understood.

Results

We employed molecular and pharmacological tools to investigate the role of tonic inhibition during epileptogenesis both in vitro and in vivo. We overexpressed two distinct subtypes of extrasynaptic GABAA receptors, α5β3γ2 and α6β3δ receptors, in cultured hippocampal neurons. We demonstrated that overexpression of both α5β3γ2 and α6β3δ receptors enhanced tonic inhibition and reduced epileptiform activity in vitro. We then showed that injection of THIP (5 μM), a selective agonist for extrasynaptic GABAA receptors at low concentration, into rat brain also suppressed epileptiform burst activity and behavioral seizures in vivo. Mechanistically, we discovered that low concentration of THIP had no effect on GABAergic synaptic transmission and did not affect the basal level of action potentials, but significantly inhibited high frequency neuronal activity induced by epileptogenic agents.

Conclusions

Our studies suggest that extrasynaptic GABAA receptors play an important role in controlling hyperexcitatory activity, such as that during epileptogenesis, but a less prominent role in modulating a low level of basal activity. We propose that tonic inhibition may play a greater role under pathological conditions than in physiological conditions in terms of modulating neural network activity.
Appendix
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Literature
1.
Duncan JS, Sander JW, Sisodiya SM, Walker MC: Adult epilepsy. Lancet. 2006, 367 (9516): 1087-1100. 10.1016/S0140-6736(06)68477-8.CrossRefPubMed
2.
3.
Farrant M, Nusser Z: Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. 2005, 6 (3): 215-229. 10.1038/nrn1625.CrossRefPubMed
4.
Mody I, Pearce RA: Diversity of inhibitory neurotransmission through GABA(A) receptors. Trends Neurosci. 2004, 27 (9): 569-575. 10.1016/j.tins.2004.07.002.CrossRefPubMed
5.
Semyanov A, Walker MC, Kullmann DM, Silver RA: Tonically active GABA A receptors: modulating gain and maintaining the tone. Trends Neurosci. 2004, 27 (5): 262-269. 10.1016/j.tins.2004.03.005.CrossRefPubMed
6.
Brunig I, Scotti E, Sidler C, Fritschy JM: Intact sorting, targeting, and clustering of gamma-aminobutyric acid A receptor subtypes in hippocampal neurons in vitro. J Comp Neurol. 2002, 443 (1): 43-55. 10.1002/cne.10102.CrossRefPubMed
7.
Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L, Bluthmann H, Mohler H, Rudolph U: Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci U S A. 2002, 99 (13): 8980-8985. 10.1073/pnas.142288699.PubMedCentralCrossRefPubMed
8.
Houser CR, Esclapez M: Downregulation of the alpha5 subunit of the GABA(A) receptor in the pilocarpine model of temporal lobe epilepsy. Hippocampus. 2003, 13 (5): 633-645. 10.1002/hipo.10108.CrossRefPubMed
9.
Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA, MacDonald JF, Orser BA: 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. 2004, 101 (10): 3662-3667. 10.1073/pnas.0307231101.PubMedCentralCrossRefPubMed
10.
Serwanski DR, Miralles CP, Christie SB, Mehta AK, Li X, De Blas AL: Synaptic and nonsynaptic localization of GABAA receptors containing the alpha5 subunit in the rat brain. J Comp Neurol. 2006, 499 (3): 458-470. 10.1002/cne.21115.PubMedCentralCrossRefPubMed
11.
Wei W, Zhang N, Peng Z, Houser CR, Mody I: Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci. 2003, 23 (33): 10650-10661.PubMed
12.
Nusser Z, Sieghart W, Somogyi P: Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J Neurosci. 1998, 18 (5): 1693-1703.PubMed
13.
Stell BM, Brickley SG, Tang CY, Farrant M, Mody I: Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc Natl Acad Sci U S A. 2003, 100 (24): 14439-14444. 10.1073/pnas.2435457100.PubMedCentralCrossRefPubMed
14.
Casula MA, Bromidge FA, Pillai GV, Wingrove PB, Martin K, Maubach K, Seabrook GR, Whiting PJ, Hadingham KL: Identification of amino acid residues responsible for the alpha5 subunit binding selectivity of L-655,708, a benzodiazepine binding site ligand at the GABA(A) receptor. J Neurochem. 2001, 77 (2): 445-451. 10.1046/j.1471-4159.2001.00289.x.CrossRefPubMed
15.
Atack JR, Bayley PJ, Seabrook GR, Wafford KA, McKernan RM, Dawson GR: L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors. Neuropharmacology. 2006, 51 (6): 1023-1029. 10.1016/j.neuropharm.2006.04.018.CrossRefPubMed
16.
Nusser Z, Mody I: Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J Neurophysiol. 2002, 87 (5): 2624-2628.PubMed
17.
Cope DW, Hughes SW, Crunelli V: GABAA receptor-mediated tonic inhibition in thalamic neurons. J Neurosci. 2005, 25 (50): 11553-11563. 10.1523/JNEUROSCI.3362-05.2005.CrossRefPubMed
18.
Wohlfarth KM, Bianchi MT, Macdonald RL: Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the delta subunit. J Neurosci. 2002, 22 (5): 1541-1549.PubMed
19.
Belelli D, Harrison NL, Maguire J, Macdonald RL, Walker MC, Cope DW: Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci. 2009, 29 (41): 12757-12763. 10.1523/JNEUROSCI.3340-09.2009.PubMedCentralCrossRefPubMed
20.
Sperk G, Furtinger S, Schwarzer C, Pirker S: GABA and its receptors in epilepsy. Adv Exp Med Biol. 2004, 548: 92-103. 10.1007/978-1-4757-6376-8_7.CrossRefPubMed
21.
Mann EO, Mody I: The multifaceted role of inhibition in epilepsy: seizure-genesis through excessive GABAergic inhibition in autosomal dominant nocturnal frontal lobe epilepsy. Curr Opin Neurol. 2008, 21 (2): 155-160. 10.1097/WCO.0b013e3282f52f5f.CrossRefPubMed
22.
Coulter DA, Carlson GC: Functional regulation of the dentate gyrus by GABA-mediated inhibition. Prog Brain Res. 2007, 163: 235-243.CrossRefPubMed
23.
Sierra-Paredes G, Sierra-Marcuno G: Extrasynaptic GABA and glutamate receptors in epilepsy. CNS Neurol Disord Drug Targets. 2007, 6 (4): 288-300. 10.2174/187152707781387251.CrossRefPubMed
24.
Richerson GB: Looking for GABA in all the wrong places: the relevance of extrasynaptic GABA(A) receptors to epilepsy. Epilepsy Curr. 2004, 4 (6): 239-242. 10.1111/j.1535-7597.2004.46008.x.PubMedCentralCrossRefPubMed
25.
Peng Z, Huang CS, Stell BM, Mody I, Houser CR: Altered expression of the delta subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J Neurosci. 2004, 24 (39): 8629-8639. 10.1523/JNEUROSCI.2877-04.2004.CrossRefPubMed
26.
Zhang N, Wei W, Mody I, Houser CR: Altered localization of GABA(A) receptor subunits on dentate granule cell dendrites influences tonic and phasic inhibition in a mouse model of epilepsy. J Neurosci. 2007, 27 (28): 7520-7531. 10.1523/JNEUROSCI.1555-07.2007.CrossRefPubMed
27.
Goodkin HP, Joshi S, Mtchedlishvili Z, Brar J, Kapur J: Subunit-specific trafficking of GABA(A) receptors during status epilepticus. J Neurosci. 2008, 28 (10): 2527-2538. 10.1523/JNEUROSCI.3426-07.2008.PubMedCentralCrossRefPubMed
28.
Rajasekaran K, Joshi S, Sun C, Mtchedlishvilli Z, Kapur J: Receptors with low affinity for neurosteroids and GABA contribute to tonic inhibition of granule cells in epileptic animals. Neurobiol Dis. 2010, 40 (2): 490-501. 10.1016/j.nbd.2010.07.016.PubMedCentralCrossRefPubMed
29.
Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, Jenkins M, Petrou S, Sutherland GR, Scheffer IE, Berkovic SF, Macdonald RL, Mulley JC: GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet. 2004, 13 (13): 1315-1319. 10.1093/hmg/ddh146.CrossRefPubMed
30.
Feng HJ, Kang JQ, Song L, Dibbens L, Mulley J, Macdonald RL: Delta subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of alpha4beta2delta GABAA receptors. J Neurosci. 2006, 26 (5): 1499-1506. 10.1523/JNEUROSCI.2913-05.2006.CrossRefPubMed
31.
Maguire JL, Stell BM, Rafizadeh M, Mody I: Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci. 2005, 8 (6): 797-804. 10.1038/nn1469.CrossRefPubMed
32.
Scimemi A, Semyanov A, Sperk G, Kullmann DM, Walker MC: Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus. J Neurosci. 2005, 25 (43): 10016-10024. 10.1523/JNEUROSCI.2520-05.2005.CrossRefPubMed
33.
Cope DW, Di Giovanni G, Fyson SJ, Orban G, Errington AC, Lorincz ML, Gould TM, Carter DA, Crunelli V: Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009, 15 (12): 1392-1398. 10.1038/nm.2058.PubMedCentralCrossRefPubMed
34.
Qi JS, Yao J, Fang C, Luscher B, Chen G: Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures. J Physiol. 2006, 577 (Pt 2): 579-590.PubMedCentralCrossRefPubMed
35.
Bai D, Zhu G, Pennefather P, Jackson MF, MacDonald JF, Orser BA: Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons. Mol Pharmacol. 2001, 59 (4): 814-824.PubMed
36.
Qi J, Wang Y, Jiang M, Warren P, Chen G: Cyclothiazide induces robust epileptiform activity in rat hippocampal neurons both in vitro and in vivo. J Physiol. 2006, 571 (Pt 3): 605-618.PubMedCentralCrossRefPubMed
37.
Wang Y, Qi JS, Kong S, Sun Y, Fan J, Jiang M, Chen G: BDNF-TrkB signaling pathway mediates the induction of epileptiform activity induced by a convulsant drug cyclothiazide. Neuropharmacology. 2009, 57 (1): 49-59. 10.1016/j.neuropharm.2009.04.007.PubMedCentralCrossRefPubMed
38.
39.
Qian B, Sun Y, Wu Z, Wan L, Chen L, Kong S, Zhang B, Zhang F, Wang ZY, Wang Y: Epileptiform response of CA1 neurones to convulsant stimulation by cyclothiazide, kainic acid and pentylenetetrazol in anaesthetized rats. Seizure. 2011, 20: 312-319. 10.1016/j.seizure.2010.12.016.CrossRefPubMed
40.
Lindquist CE, Ebert B, Birnir B: Extrasynaptic GABA(A) channels activated by THIP are modulated by diazepam in CA1 pyramidal neurons in the rat brain hippocampal slice. Mol Cell Neurosci. 2003, 24 (1): 250-257. 10.1016/S1044-7431(03)00128-3.CrossRefPubMed
41.
Krogsgaard-Larsen P, Frolund B, Liljefors T, Ebert B: GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic. Biochem Pharmacol. 2004, 68 (8): 1573-1580. 10.1016/j.bcp.2004.06.040.CrossRefPubMed
42.
Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA: Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors. Br J Pharmacol. 2002, 136 (7): 965-974. 10.1038/sj.bjp.0704795.PubMedCentralCrossRefPubMed
43.
Wafford KA, Ebert B: Gaboxadol–a new awakening in sleep. Curr Opin Pharmacol. 2006, 6 (1): 30-36. 10.1016/j.coph.2005.10.004.CrossRefPubMed
44.
Spigelman I, Li Z, Banerjee PK, Mihalek RM, Homanics GE, Olsen RW: Behavior and physiology of mice lacking the GABAA-receptor delta subunit. Epilepsia. 2002, 43 (Suppl 5): 3-8.CrossRefPubMed
45.
Cavelier P, Hamann M, Rossi D, Mobbs P, Attwell D: Tonic excitation and inhibition of neurons: ambient transmitter sources and computational consequences. Prog Biophys Mol Biol. 2005, 87 (1): 3-16. 10.1016/j.pbiomolbio.2004.06.001.CrossRefPubMed
46.
Glykys J, Mody I: Activation of GABAA receptors: views from outside the synaptic cleft. Neuron. 2007, 56 (5): 763-770. 10.1016/j.neuron.2007.11.002.CrossRefPubMed
47.
Mitchell SJ, Silver RA: Shunting inhibition modulates neuronal gain during synaptic excitation. Neuron. 2003, 38 (3): 433-445. 10.1016/S0896-6273(03)00200-9.CrossRefPubMed
48.
Chadderton P, Margrie TW, Hausser M: Integration of quanta in cerebellar granule cells during sensory processing. Nature. 2004, 428 (6985): 856-860. 10.1038/nature02442.CrossRefPubMed
49.
Fritschy JM, Kiener T, Bouilleret V, Loup F: GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy. Neurochem Int. 1999, 34 (5): 435-445. 10.1016/S0197-0186(99)00040-6.CrossRefPubMed
50.
Houser CR, Esclapez M: Vulnerability and plasticity of the GABA system in the pilocarpine model of spontaneous recurrent seizures. Epilepsy Res. 1996, 26 (1): 207-218. 10.1016/S0920-1211(96)00054-X.CrossRefPubMed
51.
52.
Krook-Magnuson EI, Li P, Paluszkiewicz SM, Huntsman MM: Tonically active inhibition selectively controls feedforward circuits in mouse barrel cortex. J Neurophysiol. 2008, 100 (2): 932-944. 10.1152/jn.01360.2007.PubMedCentralCrossRefPubMed
53.
Gao H, Smith BN: Tonic GABAA receptor-mediated inhibition in the rat dorsal motor nucleus of the vagus. J Neurophysiol. 2010, 103 (2): 904-914. 10.1152/jn.00511.2009.PubMedCentralCrossRefPubMed
54.
Olmos-Serrano JL, Paluszkiewicz SM, Martin BS, Kaufmann WE, Corbin JG, Huntsman MM: Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J Neurosci. 2010, 30 (29): 9929-9938. 10.1523/JNEUROSCI.1714-10.2010.PubMedCentralCrossRefPubMed
55.
Edwards MD, White AM, Platt B: Characterisation of rat superficial superior colliculus neurones: firing properties and sensitivity to GABA. Neuroscience. 2002, 110 (1): 93-104. 10.1016/S0306-4522(01)00558-9.CrossRefPubMed
56.
Judge SJ, Ingram CD, Gartside SE: GABA receptor modulation of 5-HT neuronal firing: characterization and effect of moderate in vivo variations in glucocorticoid levels. Neurochem Int. 2004, 45 (7): 1057-1065. 10.1016/j.neuint.2004.05.003.CrossRefPubMed
57.
Storustovu SI, Ebert B: Pharmacological characterization of agonists at delta-containing GABAA receptors: Functional selectivity for extrasynaptic receptors is dependent on the absence of gamma2. J Pharmacol Exp Ther. 2006, 316 (3): 1351-1359.CrossRefPubMed
58.
Cremers T, Ebert B: Plasma and CNS concentrations of Gaboxadol in rats following subcutaneous administration. Eur J Pharmacol. 2007, 562 (1–2): 47-52.CrossRefPubMed
59.
Pavlov I, Savtchenko LP, Kullmann DM, Semyanov A, Walker MC: Outwardly rectifying tonically active GABAA receptors in pyramidal cells modulate neuronal offset, not gain. J Neurosci. 2009, 29 (48): 15341-15350. 10.1523/JNEUROSCI.2747-09.2009.CrossRefPubMed
60.
Jiang M, Chen G: High Ca2+−phosphate transfection efficiency in low-density neuronal cultures. Nat Protoc. 2006, 1 (2): 695-700. 10.1038/nprot.2006.86.CrossRefPubMed
61.
Wheal HV, Bernard C, Chad JE, Cannon RC: Pro-epileptic changes in synaptic function can be accompanied by pro-epileptic changes in neuronal excitability. Trends Neurosci. 1998, 21 (4): 167-174. 10.1016/S0166-2236(97)01182-X.CrossRefPubMed
62.
Racine RJ: Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol. 1972, 32 (3): 281-294. 10.1016/0013-4694(72)90177-0.CrossRefPubMed
Metadata
Title
Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors
Authors
Yajie Sun
Zheng Wu
Shuzhen Kong
Dongyun Jiang
Anar Pitre
Yun Wang
Gong Chen
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Brain / Issue 1/2013
Electronic ISSN: 1756-6606
DOI
https://doi.org/10.1186/1756-6606-6-21

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