Enhanced tonic GABAA inhibition in typical absence epilepsy

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Abstract

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.

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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.

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Acknowledgements

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)

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