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Enhanced tonic GABAA inhibition in typical absence epilepsy.

Cope DW, Di Giovanni G, Fyson SJ, Orbán G, Errington AC, Lorincz ML, Gould TM, Carter DA, Crunelli V - Nat. Med. (2009)

Bottom Line: The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired gamma-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis.In contrast, we show here that extrasynaptic GABA(A) 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.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, Cardiff University, Cardiff, UK.

ABSTRACT
The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired gamma-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABA(A) 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 GABA(A) receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABA(A) 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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δ subunit knockout mice exhibit reduced tonic inhibition and reduced sensitivity to GBL–induced SWDs. (a) Representative current traces from P23–30 wildtype (WT, left) and δ subunit knockout (δ KO, right) mice revealing tonic currents following the focal application of 100 μM GBZ (white bars). (b) Comparison of tonic current amplitude in WT (white column) and δ KO (black column) mice. Number of recorded neurons are as indicated. (c) Comparison of normalised tonic current amplitude for the same neurons as in (b). (d) Simultaneous, bilateral EEG traces from WT (left) and δ KO (right) mice under control conditions (top) and following injection of GBL (50 mg kg−1 i.p., bottom). (e) Graph showing the effects of GBL on the time (15 min periods) spent in seizure for WT compared to δ KO mice. (f) Comparison of the total time spent in GBL–induced seizure (over 1 hr) between WT and δ KO mice, and the effect of ETX (200 mg kg−1 i.p.) on seizures in WT mice. Number of recorded animals in (f) is the same as in (e). * P < 0.05, ** P < 0.01 and *** P < 0.001.
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Figure 4: δ subunit knockout mice exhibit reduced tonic inhibition and reduced sensitivity to GBL–induced SWDs. (a) Representative current traces from P23–30 wildtype (WT, left) and δ subunit knockout (δ KO, right) mice revealing tonic currents following the focal application of 100 μM GBZ (white bars). (b) Comparison of tonic current amplitude in WT (white column) and δ KO (black column) mice. Number of recorded neurons are as indicated. (c) Comparison of normalised tonic current amplitude for the same neurons as in (b). (d) Simultaneous, bilateral EEG traces from WT (left) and δ KO (right) mice under control conditions (top) and following injection of GBL (50 mg kg−1 i.p., bottom). (e) Graph showing the effects of GBL on the time (15 min periods) spent in seizure for WT compared to δ KO mice. (f) Comparison of the total time spent in GBL–induced seizure (over 1 hr) between WT and δ KO mice, and the effect of ETX (200 mg kg−1 i.p.) on seizures in WT mice. Number of recorded animals in (f) is the same as in (e). * P < 0.05, ** P < 0.01 and *** P < 0.001.

Mentions: To assess the importance of enhanced eGABAAR function to seizure generation in two well established models of absence epilepsy, GHB and GAERS, we performed two sets of experiments. Firstly, we determined whether animals without thalamic eGABAARs were resistant to the pharmacological induction of absence seizures. GABAAR δ subunit knockout (δ KO) mice have reduced tonic inhibition in TC neurons (P < 0.01–0.001) (Fig. 4a–c)39, whereas sIPSCs are largely unaffected (Supplementary Table 3), and preliminary findings indicate these mice are resistant to the induction of SWDs by GHB and low concentrations of pentylenetetrazole40. In WT littermates, systemic administration of the GHB pro–drug γ–butyrolactone (GBL, 50 mg kg–1 i.p.)41 readily induced absence seizures (Fig. 4d,e) that were largely abolished following administration of ETX (200 mg kg–1 i.p., P < 0.001) (Fig. 4f). However, GBL administration only rarely induced SWDs in δ KO mice (Fig. 4d-f).


Enhanced tonic GABAA inhibition in typical absence epilepsy.

Cope DW, Di Giovanni G, Fyson SJ, Orbán G, Errington AC, Lorincz ML, Gould TM, Carter DA, Crunelli V - Nat. Med. (2009)

δ subunit knockout mice exhibit reduced tonic inhibition and reduced sensitivity to GBL–induced SWDs. (a) Representative current traces from P23–30 wildtype (WT, left) and δ subunit knockout (δ KO, right) mice revealing tonic currents following the focal application of 100 μM GBZ (white bars). (b) Comparison of tonic current amplitude in WT (white column) and δ KO (black column) mice. Number of recorded neurons are as indicated. (c) Comparison of normalised tonic current amplitude for the same neurons as in (b). (d) Simultaneous, bilateral EEG traces from WT (left) and δ KO (right) mice under control conditions (top) and following injection of GBL (50 mg kg−1 i.p., bottom). (e) Graph showing the effects of GBL on the time (15 min periods) spent in seizure for WT compared to δ KO mice. (f) Comparison of the total time spent in GBL–induced seizure (over 1 hr) between WT and δ KO mice, and the effect of ETX (200 mg kg−1 i.p.) on seizures in WT mice. Number of recorded animals in (f) is the same as in (e). * P < 0.05, ** P < 0.01 and *** P < 0.001.
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Figure 4: δ subunit knockout mice exhibit reduced tonic inhibition and reduced sensitivity to GBL–induced SWDs. (a) Representative current traces from P23–30 wildtype (WT, left) and δ subunit knockout (δ KO, right) mice revealing tonic currents following the focal application of 100 μM GBZ (white bars). (b) Comparison of tonic current amplitude in WT (white column) and δ KO (black column) mice. Number of recorded neurons are as indicated. (c) Comparison of normalised tonic current amplitude for the same neurons as in (b). (d) Simultaneous, bilateral EEG traces from WT (left) and δ KO (right) mice under control conditions (top) and following injection of GBL (50 mg kg−1 i.p., bottom). (e) Graph showing the effects of GBL on the time (15 min periods) spent in seizure for WT compared to δ KO mice. (f) Comparison of the total time spent in GBL–induced seizure (over 1 hr) between WT and δ KO mice, and the effect of ETX (200 mg kg−1 i.p.) on seizures in WT mice. Number of recorded animals in (f) is the same as in (e). * P < 0.05, ** P < 0.01 and *** P < 0.001.
Mentions: To assess the importance of enhanced eGABAAR function to seizure generation in two well established models of absence epilepsy, GHB and GAERS, we performed two sets of experiments. Firstly, we determined whether animals without thalamic eGABAARs were resistant to the pharmacological induction of absence seizures. GABAAR δ subunit knockout (δ KO) mice have reduced tonic inhibition in TC neurons (P < 0.01–0.001) (Fig. 4a–c)39, whereas sIPSCs are largely unaffected (Supplementary Table 3), and preliminary findings indicate these mice are resistant to the induction of SWDs by GHB and low concentrations of pentylenetetrazole40. In WT littermates, systemic administration of the GHB pro–drug γ–butyrolactone (GBL, 50 mg kg–1 i.p.)41 readily induced absence seizures (Fig. 4d,e) that were largely abolished following administration of ETX (200 mg kg–1 i.p., P < 0.001) (Fig. 4f). However, GBL administration only rarely induced SWDs in δ KO mice (Fig. 4d-f).

Bottom Line: The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired gamma-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis.In contrast, we show here that extrasynaptic GABA(A) 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.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, Cardiff University, Cardiff, UK.

ABSTRACT
The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired gamma-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABA(A) 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 GABA(A) receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABA(A) 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.

Show MeSH
Related in: MedlinePlus