Enhanced tonic GABAA inhibition in typical absence epilepsy

Article metrics


The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired γ-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent 'tonic' inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT-1 in the genetic models tested, and GAT-1 is crucial in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioral correlates of seizures in normal rats. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic importance and highlight potential therapeutic targets for the treatment of absence epilepsy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Increased tonic GABAA inhibition in genetic and pharmacological models of absence seizures.
Figure 2: Aberrant GABA uptake by GAT-1 underlies enhanced tonic inhibition in GAERS, stargazer and lethargic.
Figure 3: Role of thalamic GAT-1 in the generation of SWDs.
Figure 4: δ subunit–knockout mice show reduced tonic inhibition and reduced sensitivity to γ-butyrolactone (GBL)-induced SWDs.
Figure 5: Spontaneous absence seizures in GAERS are reduced by intrathalamic injection of δ subunit–specific antisense oligodeoxynucleotides (ODNs).
Figure 6: Selective activation of thalamic eGABAARs initiates absence seizures in normal Wistar rats.


  1. 1

    Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30, 389–399 (1989).

  2. 2

    Crunelli, V. & Leresche, N. Childhood absence epilepsy: genes, channels, neurons and networks. Nat. Rev. Neurosci. 3, 371–382 (2002).

  3. 3

    McCormick, D.A. & Contreras, D. On the cellular and network bases of epileptic seizures. Annu. Rev. Physiol. 63, 815–846 (2001).

  4. 4

    Blumenfeld, H. Cellular and network mechanisms of spike-wave seizures. Epilepsia 46 Suppl 9, 21–33 (2005).

  5. 5

    von Krosigk, M., Bal, T. & McCormick, D.A. Cellular mechanisms of a synchronized oscillation in the thalamus. Science 261, 361–364 (1993).

  6. 6

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

  7. 7

    Wallace, R.H. et al. Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nat. Genet. 28, 49–52 (2001).

  8. 8

    Kananura, C. et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch. Neurol. 59, 1137–1141 (2002).

  9. 9

    Maljevic, S. et al. A mutation in the GABAA receptor α1-subunit is associated with absence epilepsy. Ann. Neurol. 59, 983–987 (2006).

  10. 10

    Macdonald, R.L., Gallagher, M.J., Feng, H.-J. & Kang, J. GABAA receptor epilepsy mutations. Biochem. Pharmacol. 68, 1497–1506 (2004).

  11. 11

    Caddick, S.J. et al. Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4lh) and tottering (Cacna1atg) mouse thalami. J. Neurophysiol. 81, 2066–2074 (1999).

  12. 12

    Bessaïh, T. et al. Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures. J. Neurophysiol. 96, 3074–3081 (2006).

  13. 13

    Tan, H.O. et al. Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy. Proc. Natl. Acad. Sci. USA 104, 17536–17541 (2007).

  14. 14

    Hosford, D.A., Wang, Y. & Cao, Z. Differential effects mediated by GABAA receptors in thalamic nuclei in lh/lh model of absence seizures. Epilepsy Res. 27, 55–65 (1997).

  15. 15

    Hosford, D.A. & Wang, Y. Utility of the lethargic (lh/lh) mouse model of absence seizures in predicting the effects of lamotrigine, vigabatrin, tiagabine, gabapentin and topiramate against human absence seizures. Epilepsia 38, 408–414 (1997).

  16. 16

    Danober, L., Deransart, C., Depaulis, A., Vergnes, M. & Marescaux, C. Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog. Neurobiol. 55, 27–57 (1998).

  17. 17

    Perucca, E., Gram, L., Avanzini, G. & Dulac, O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 39, 5–17 (1998).

  18. 18

    Ettinger, A.B. et al. Two cases of nonconvulsive status epilepticus in association with tiagabine therapy. Epilepsia 40, 1159–1162 (1999).

  19. 19

    Farrant, M. & Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat. Rev. Neurosci. 6, 215–229 (2005).

  20. 20

    Glykys, J. & Mody, I. Activation of GABAA receptors: views from outside the synaptic cleft. Neuron 56, 763–770 (2007).

  21. 21

    Belelli, D., Peden, D.R., Rosahl, T.W., Wafford, K.A. & Lambert, J.J. Extrasynaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics. J. Neurosci. 25, 11513–11520 (2005).

  22. 22

    Cope, D.W., Hughes, S.W. & Crunelli, V. GABAA receptor–mediated tonic inhibition in thalamic neurons. J. Neurosci. 25, 11553–11563 (2005).

  23. 23

    Jia, F. et al. An extrasynaptic GABAA receptor mediates tonic inhibition in thalamic VB neurons. J. Neurophysiol. 94, 4491–4501 (2005).

  24. 24

    Bright, D.P., Aller, M.I. & Brickley, S.G. Synaptic release generates a tonic GABAA receptor–mediated conductance that modulates burst precision in thalamic relay neurons. J. Neurosci. 27, 2560–2569 (2007).

  25. 25

    Laurie, D.J., Wisden, W. & Seeburg, P.H. The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J. Neurosci. 12, 4151–4172 (1992).

  26. 26

    Fletcher, C.F. & Frankel, W.N. Ataxic mouse mutants and molecular mechanisms of absence epilepsy. Hum. Mol. Genet. 8, 1907–1912 (1999).

  27. 27

    Snead, O.C., III. The γ-hydroxybutyrate model of absence seizures: correlation of regional brain levels of γ-hydroxybutyric acid and γ-butyrolactone with spike wave discharges. Neuropharmacology 30, 161–167 (1991).

  28. 28

    Banerjee, P.K., Hirsch, E. & Snead, O.C., III. γ-hydroxybutyric acid induced spike and wave discharges in rats: relation to high-affinity [3H]γ-hydroxybutyric acid binding sites in the thalamus and cortex. Neuroscience 56, 11–21 (1993).

  29. 29

    Fariello, R.G. & Golden, G.T. The THIP-induced model of bilateral synchronous spike and wave in rodents. Neuropharmacology 26, 161–165 (1987).

  30. 30

    Le Feuvre, Y., Fricker, D. & Leresche, N. GABAA receptor–mediated IPSCs in rat thalamic sensory nuclei: patterns of discharge and tonic modulation by GABAB autoreceptors. J. Physiol. (Lond.) 502, 91–104 (1997).

  31. 31

    Richards, D.A., Lemos, T., Whitton, P.S. & Bowery, N.G. Extracellular GABA in the ventrolateral thalamus of rats exhibiting spontaneous absence epilepsy: a microdialysis study. J. Neurochem. 65, 1674–1680 (1995).

  32. 32

    Sutch, R.J., Davies, C.C. & Bowery, N.G. GABA release and uptake measured in crude synaptosomes from Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Neurochem. Int. 34, 415–425 (1999).

  33. 33

    Borden, L.A. GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem. Int. 29, 335–356 (1996).

  34. 34

    De Biasi, S., Vitellaro-Zuccarello, L. & Brecha, N.C. Immunoreactivity for the GABA transporter-1 and GABA transporter-3 is restricted to astrocytes in the rat thalamus. A light and electron-microscopic immunolocalization. Neuroscience 83, 815–828 (1998).

  35. 35

    Pow, D.V. et al. Differential expression of the GABA transporters GAT-1 and GAT-3 in brains of rats, cats, monkeys and humans. Cell Tissue Res. 320, 379–392 (2005).

  36. 36

    Wu, Y., Wang, W., Díez-Sampdero, A. & Richerson, G.B. Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1. Neuron 56, 851–865 (2007).

  37. 37

    Chiu, C.-S. et al. GABA transporter deficiency causes tremor, ataxia, nervousness and increased GABA-induced tonic conductance in cerebellum. J. Neurosci. 25, 3234–3245 (2005).

  38. 38

    Bragina, L. et al. GAT-1 regulates both tonic and phasic GABAA receptor-mediated inhibition in the cerebral cortex. J. Neurochem. 105, 1781–1793 (2008).

  39. 39

    Herd, M.B. et al. Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for δ-GABAA receptors. Eur. J. Neurosci. 29, 1177–1187 (2009).

  40. 40

    Aizawa, M., Ito, Y. & Fukuda, H. Pharmacological profiles of generalized absence seizures in lethargic, stargazer and γ-hydroxybutyrate–treated model mice. Neurosci. Res. 29, 17–25 (1997).

  41. 41

    Maguire, J.L., Stell, B.M., Rafizadeh, M. & Mody, I. Ovarian cycle–linked changes in GABAA receptors mediating tonic inhibition alter seizures susceptibility and anxiety. Nat. Neurosci. 8, 797–804 (2005).

  42. 42

    Stórustovu, S.I. & Ebert, B. Pharmacological characterization of agonists at δ-containing GABAA receptors: functional selectivity for extrasynaptic receptors is dependent on the absence of γ2. J. Pharmacol. Exp. Ther. 316, 1351–1359 (2006).

  43. 43

    Quick, M.W., Corey, J.L., Davidson, N. & Lester, H.A. Second messengers, trafficking-related proteins and amino acid residues that contribute to the functional regulation of the rat brain GABA transporter GAT1. J. Neurosci. 17, 2967–2979 (1997).

  44. 44

    Beckman, M.L., Bernstein, E.M. & Quick, M.W. Multiple G protein–coupled receptors initiate protein kinase C redistribution of GABA transporters in hippocampal neurons. J. Neurosci. 19, RC9 (1999).

  45. 45

    Wang, D., Deken, S.L., Whitworth, T.L. & Quick, M.W. Syntaxin 1A inhibits GABA flux, efflux and exchange mediated by the rat brain GABA transporter GAT1. Mol. Pharmacol. 64, 905–913 (2003).

  46. 46

    Hu, J. & Quick, M.W. Substrate-mediated regulation of γ-aminobutyric acid transporter 1 in rat brain. Neuropharmacology 54, 309–318 (2008).

  47. 47

    Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates 2nd edn. (Academic Press, San Diego, 1986).

  48. 48

    Juhász, G., Kékesi, K., Emri, Z., Soltesz, I. & Crunelli, V. Sleep-promoting action of excitatory amino acid antagonists: a different role for thalamic NMDA and non-NMDA receptors. Neurosci. Lett. 114, 333–338 (1990).

Download references


We thank P. Blanning for his help in genotyping mice, D. Belelli who kindly provided the genotyping protocol for the δ subunit–knockout mice and K. Thomas for initial discussions on the antisense oligodeoxynucleotide experiments. H. Parri, S. Hughes and N. Leresche commented on a previous version of the manuscript. D.W.C. is a research Fellow of Epilepsy Research UK (grant P0802), and G.O. was supported by a Fellowship of the Italian Ministry for University and Scientific Research. This work was also supported by the Wellcome Trust (grant 71436) and the European Union (grant HEALTH F2–2007–202167).

Author information

D.W.C., G.D., S.J.F., A.C.E. and V.C. designed the research; D.W.C., G.D., S.J.F., G.O., A.C.E., M.L.L., T.M.G. and D.A.C. performed the research; D.W.C., G.D., S.J.F., G.O., A.C.E. and D.A.C. analyzed the data; and D.W.C. and V.C. wrote the paper.

Correspondence to David W Cope or Vincenzo Crunelli.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Tables 1–3, Supplementary Results, Supplementary Discussion and Supplementary Methods (PDF 3637 kb)

Supplementary Movie 1

Movie showing the occurrence of absence seizures in a normal Wistar rat during the intra-thalamic administration of 200 μM NO711. Note the strict time correlation between the behavioural components of the seizures (immobility and twitching of the vibrissae) and the appearance of large amplitude SWDs in the EEG, as depicted on the oscilloscope. (MOV 914 kb)

Supplementary Movie 2

Movie showing the occurrence of a number of absence seizures induced by the intra-thalamic administration of 100 μM THIP in a normal Wistar rat. The appearance of SWDs in the EGG correlates with the behavioural components of the seizures, including immobility, head and neck jerks, and twitching of vibrissae. Note the lack of head and neck jerks during the first seizure. (MOV 2907 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading