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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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Increased tonic GABAA inhibition in genetic and pharmacological models of absence seizures. (a) Representative current traces from TC neurons of P14 (upper panels) and P17 (lower panels) NEC and GAERS, indicating the presence of tonic GABAA currents following the focal application of 100 μM gabazine (GBZ, white bars). Dotted lines indicate the continuation of the initial baseline current for each neuron. (b) Comparison of the tonic current amplitude in NEC (white columns) and GAERS (black columns) at the ages indicated (P14 to P29/30). (c) Comparison of tonic current amplitude in post–seizure stargazer (stg, P19–21, light grey column), lethargic (lh, P27–30, grey column) and tottering (tg, P26–28, dark grey column) mice to respective control littermates of the same age (LIT., white columns). (d) Representative current trace from a normal Wistar rat TC neuron showing the effect of 3 μM THIP on baseline current in the presence of 0.5 μM TTX. The dotted line indicates the initial baseline current. (e) Comparison of tonic current amplitude in varying concentrations of THIP. (f) Representative current traces, in the presence of 0.5 μM TTX, from two different Wistar TC neurons showing the effect of 3 mM GHB (right) on tonic current amplitude compared to control (left). (g) Comparison of the effects of varying concentrations of GHB on tonic current amplitude, and block of GHB–induced increases by the GABABR antagonist CGP55845 (10 μM) and the putative GHB receptor antagonist NCS–382 (1 mM). Values were normalised to the average tonic current amplitude under control conditions. Experiments in (d–g) were performed on P21–26 Wistar rats. * P < 0.05, ** P < 0.01, *** P < 0.001. For (b), (c), (e) and (g), the number of recorded neurons is as indicated.
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Figure 1: Increased tonic GABAA inhibition in genetic and pharmacological models of absence seizures. (a) Representative current traces from TC neurons of P14 (upper panels) and P17 (lower panels) NEC and GAERS, indicating the presence of tonic GABAA currents following the focal application of 100 μM gabazine (GBZ, white bars). Dotted lines indicate the continuation of the initial baseline current for each neuron. (b) Comparison of the tonic current amplitude in NEC (white columns) and GAERS (black columns) at the ages indicated (P14 to P29/30). (c) Comparison of tonic current amplitude in post–seizure stargazer (stg, P19–21, light grey column), lethargic (lh, P27–30, grey column) and tottering (tg, P26–28, dark grey column) mice to respective control littermates of the same age (LIT., white columns). (d) Representative current trace from a normal Wistar rat TC neuron showing the effect of 3 μM THIP on baseline current in the presence of 0.5 μM TTX. The dotted line indicates the initial baseline current. (e) Comparison of tonic current amplitude in varying concentrations of THIP. (f) Representative current traces, in the presence of 0.5 μM TTX, from two different Wistar TC neurons showing the effect of 3 mM GHB (right) on tonic current amplitude compared to control (left). (g) Comparison of the effects of varying concentrations of GHB on tonic current amplitude, and block of GHB–induced increases by the GABABR antagonist CGP55845 (10 μM) and the putative GHB receptor antagonist NCS–382 (1 mM). Values were normalised to the average tonic current amplitude under control conditions. Experiments in (d–g) were performed on P21–26 Wistar rats. * P < 0.05, ** P < 0.01, *** P < 0.001. For (b), (c), (e) and (g), the number of recorded neurons is as indicated.

Mentions: Genetic absence epilepsy rats from Strasbourg (GAERS) are a well established polygenic model of absence epilepsy, that exhibit bilateral spontaneous SWDs and accompanying behavioural arrest from approximately postnatal day (P)30 (ref. 16). In TC neurons, tonic GABAA currents are generated by extrasynaptic receptors containing the δ subunit21-23, and in rats significant levels of δ subunit are apparent only from ~P12 (ref. 25). Therefore, we measured tonic GABAA current amplitude from TC neurons in slices of the somatosensory ventrobasal (VB) thalamus of GAERS from P14 onward, and compared it to non–epileptic control (NEC) animals of the same age. No significant difference in tonic current amplitude was observed at P14–16 (P > 0.05 for each day) (Fig. 1a,b). At P17, however, there was an approximate two–fold increase in tonic current amplitude in GAERS compared to NEC (P < 0.05), that was sustained in subsequent days (Fig. 1a,b), and was independent of whole–cell capacitance (Supplementary Results and Supplementary Fig. 1a). Comparison of spontaneous IPSC (sIPSC) parameters in GAERS and NEC at the same ages revealed no consistent differences (Supplementary Table 1), in agreement with previous data obtained from younger GAERS12. Interestingly, there was a significantly smaller sIPSC peak amplitude, frequency, charge transfer and total current in GAERS at P18, but these changes were not maintained at later ages (Supplementary Table 1). These results show that TC neurons of GAERS exhibit a selective enhancement of eGABAAR function prior to seizure onset.


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)

Increased tonic GABAA inhibition in genetic and pharmacological models of absence seizures. (a) Representative current traces from TC neurons of P14 (upper panels) and P17 (lower panels) NEC and GAERS, indicating the presence of tonic GABAA currents following the focal application of 100 μM gabazine (GBZ, white bars). Dotted lines indicate the continuation of the initial baseline current for each neuron. (b) Comparison of the tonic current amplitude in NEC (white columns) and GAERS (black columns) at the ages indicated (P14 to P29/30). (c) Comparison of tonic current amplitude in post–seizure stargazer (stg, P19–21, light grey column), lethargic (lh, P27–30, grey column) and tottering (tg, P26–28, dark grey column) mice to respective control littermates of the same age (LIT., white columns). (d) Representative current trace from a normal Wistar rat TC neuron showing the effect of 3 μM THIP on baseline current in the presence of 0.5 μM TTX. The dotted line indicates the initial baseline current. (e) Comparison of tonic current amplitude in varying concentrations of THIP. (f) Representative current traces, in the presence of 0.5 μM TTX, from two different Wistar TC neurons showing the effect of 3 mM GHB (right) on tonic current amplitude compared to control (left). (g) Comparison of the effects of varying concentrations of GHB on tonic current amplitude, and block of GHB–induced increases by the GABABR antagonist CGP55845 (10 μM) and the putative GHB receptor antagonist NCS–382 (1 mM). Values were normalised to the average tonic current amplitude under control conditions. Experiments in (d–g) were performed on P21–26 Wistar rats. * P < 0.05, ** P < 0.01, *** P < 0.001. For (b), (c), (e) and (g), the number of recorded neurons is as indicated.
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Related In: Results  -  Collection

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Figure 1: Increased tonic GABAA inhibition in genetic and pharmacological models of absence seizures. (a) Representative current traces from TC neurons of P14 (upper panels) and P17 (lower panels) NEC and GAERS, indicating the presence of tonic GABAA currents following the focal application of 100 μM gabazine (GBZ, white bars). Dotted lines indicate the continuation of the initial baseline current for each neuron. (b) Comparison of the tonic current amplitude in NEC (white columns) and GAERS (black columns) at the ages indicated (P14 to P29/30). (c) Comparison of tonic current amplitude in post–seizure stargazer (stg, P19–21, light grey column), lethargic (lh, P27–30, grey column) and tottering (tg, P26–28, dark grey column) mice to respective control littermates of the same age (LIT., white columns). (d) Representative current trace from a normal Wistar rat TC neuron showing the effect of 3 μM THIP on baseline current in the presence of 0.5 μM TTX. The dotted line indicates the initial baseline current. (e) Comparison of tonic current amplitude in varying concentrations of THIP. (f) Representative current traces, in the presence of 0.5 μM TTX, from two different Wistar TC neurons showing the effect of 3 mM GHB (right) on tonic current amplitude compared to control (left). (g) Comparison of the effects of varying concentrations of GHB on tonic current amplitude, and block of GHB–induced increases by the GABABR antagonist CGP55845 (10 μM) and the putative GHB receptor antagonist NCS–382 (1 mM). Values were normalised to the average tonic current amplitude under control conditions. Experiments in (d–g) were performed on P21–26 Wistar rats. * P < 0.05, ** P < 0.01, *** P < 0.001. For (b), (c), (e) and (g), the number of recorded neurons is as indicated.
Mentions: Genetic absence epilepsy rats from Strasbourg (GAERS) are a well established polygenic model of absence epilepsy, that exhibit bilateral spontaneous SWDs and accompanying behavioural arrest from approximately postnatal day (P)30 (ref. 16). In TC neurons, tonic GABAA currents are generated by extrasynaptic receptors containing the δ subunit21-23, and in rats significant levels of δ subunit are apparent only from ~P12 (ref. 25). Therefore, we measured tonic GABAA current amplitude from TC neurons in slices of the somatosensory ventrobasal (VB) thalamus of GAERS from P14 onward, and compared it to non–epileptic control (NEC) animals of the same age. No significant difference in tonic current amplitude was observed at P14–16 (P > 0.05 for each day) (Fig. 1a,b). At P17, however, there was an approximate two–fold increase in tonic current amplitude in GAERS compared to NEC (P < 0.05), that was sustained in subsequent days (Fig. 1a,b), and was independent of whole–cell capacitance (Supplementary Results and Supplementary Fig. 1a). Comparison of spontaneous IPSC (sIPSC) parameters in GAERS and NEC at the same ages revealed no consistent differences (Supplementary Table 1), in agreement with previous data obtained from younger GAERS12. Interestingly, there was a significantly smaller sIPSC peak amplitude, frequency, charge transfer and total current in GAERS at P18, but these changes were not maintained at later ages (Supplementary Table 1). These results show that TC neurons of GAERS exhibit a selective enhancement of eGABAAR function prior to seizure onset.

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