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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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Aberrant GABA uptake by GAT–1 underlies enhanced tonic inhibition in GAERS, stargazer and lethargic. (a) Representative current traces in P18–21 NEC and GAERS showing the effects of block of GAT–1 alone (following bath application of 10 μM NO711, upper traces), GAT–3 alone (20 μM SNAP5114, middle traces), and GAT–1 and GAT–3 together (NO. + SNAP., lower traces), on tonic current amplitude, revealed by focal application of 100 μM GBZ (white bars). (b) Comparison of the effects of application of NO711 and SNAP5114 alone, and their co–application, on tonic current amplitude in NEC (white columns) and GAERS (black columns). (c) Comparison of the effect of NO711 and SNAP5114 alone, and their co–application, on tonic current amplitude in P19–21 stargazer (stg) mice (light grey columns) and control littermates (LIT., white columns). (d) Comparison of the effect of NO711 on tonic current amplitude in P27–30 lethargic (lh) mice (grey columns) and control littermates (LIT., white columns). (e) Comparison of the effect of bath application of 10 μM CGP55845 on tonic current amplitude in GAERS, stargazer and lethargic. Values were normalised to the average tonic current amplitude in the absence of CGP55845. (b), (c) and (d) * P < 0.05, ** P < 0.01 and *** P < 0.001, mutant vs. non–mutant animals under control conditions; * P < 0.05, ** P < 0.01 and *** P < 0.001, drug vs. non–drug for each strain. (e) * P < 0.05, control vs. CGP55845. For (b–e), the number of recorded neurons is as indicated.
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Figure 2: Aberrant GABA uptake by GAT–1 underlies enhanced tonic inhibition in GAERS, stargazer and lethargic. (a) Representative current traces in P18–21 NEC and GAERS showing the effects of block of GAT–1 alone (following bath application of 10 μM NO711, upper traces), GAT–3 alone (20 μM SNAP5114, middle traces), and GAT–1 and GAT–3 together (NO. + SNAP., lower traces), on tonic current amplitude, revealed by focal application of 100 μM GBZ (white bars). (b) Comparison of the effects of application of NO711 and SNAP5114 alone, and their co–application, on tonic current amplitude in NEC (white columns) and GAERS (black columns). (c) Comparison of the effect of NO711 and SNAP5114 alone, and their co–application, on tonic current amplitude in P19–21 stargazer (stg) mice (light grey columns) and control littermates (LIT., white columns). (d) Comparison of the effect of NO711 on tonic current amplitude in P27–30 lethargic (lh) mice (grey columns) and control littermates (LIT., white columns). (e) Comparison of the effect of bath application of 10 μM CGP55845 on tonic current amplitude in GAERS, stargazer and lethargic. Values were normalised to the average tonic current amplitude in the absence of CGP55845. (b), (c) and (d) * P < 0.05, ** P < 0.01 and *** P < 0.001, mutant vs. non–mutant animals under control conditions; * P < 0.05, ** P < 0.01 and *** P < 0.001, drug vs. non–drug for each strain. (e) * P < 0.05, control vs. CGP55845. For (b–e), the number of recorded neurons is as indicated.

Mentions: We next examined the mechanism(s) giving rise to enhanced tonic GABAA current in GAERS. Elevated GABA levels have been observed in the ventral thalamus of adult GAERS compared to NEC31, and may arise due to reduced GABA uptake32. Therefore, we tested the contribution of aberrant GABA uptake to enhanced tonic current in P18–21 GAERS compared to age–matched NEC using concentrations of GABA transporter blockers selective for GAT–1 and GAT–3 (ref. 33). In NEC, application of the GAT–1 blocker NO711 (10 μM) significantly increased tonic current compared to control conditions (P < 0.01) (Fig. 2a,b), and application of the GAT–3 blocker SNAP5114 (20 μM) increased tonic current (P < 0.001) to a greater extent than NO711, in agreement with the greater abundance of GAT–3 in the thalamus34,35. Co-application of NO711 and SNAP5114 in NEC increased tonic current (P < 0.001) to a greater extent than would be expected by simply summing the effects of NO711 and SNAP5114 alone, suggesting that block of GAT–1 causes a compensatory increase in uptake by GAT–3, and vice versa. In GAERS, application of NO711 had no effect on tonic current (P > 0.05) (Fig. 2a,b), but application of SNAP5114 caused a large increase (P < 0.001). Co–application of NO711 and SNAP5114 in GAERS significantly increased tonic current (P < 0.001), but the increase was similar to that observed following application of SNAP5114 alone, and following co–application of NO711 and SNAP5114 in NEC. Compromised GABA uptake by GAT–1 is therefore responsible for enhanced tonic current since (i) block of GAT–1 in GAERS has no effect on tonic current amplitude, (ii) block of GAT–1 in NEC increases tonic current amplitude to similar values to that seen in GAERS under control conditions, and (iii) the compensatory increase in uptake by GAT–1 following block of GAT–3 is lost in GAERS.


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)

Aberrant GABA uptake by GAT–1 underlies enhanced tonic inhibition in GAERS, stargazer and lethargic. (a) Representative current traces in P18–21 NEC and GAERS showing the effects of block of GAT–1 alone (following bath application of 10 μM NO711, upper traces), GAT–3 alone (20 μM SNAP5114, middle traces), and GAT–1 and GAT–3 together (NO. + SNAP., lower traces), on tonic current amplitude, revealed by focal application of 100 μM GBZ (white bars). (b) Comparison of the effects of application of NO711 and SNAP5114 alone, and their co–application, on tonic current amplitude in NEC (white columns) and GAERS (black columns). (c) Comparison of the effect of NO711 and SNAP5114 alone, and their co–application, on tonic current amplitude in P19–21 stargazer (stg) mice (light grey columns) and control littermates (LIT., white columns). (d) Comparison of the effect of NO711 on tonic current amplitude in P27–30 lethargic (lh) mice (grey columns) and control littermates (LIT., white columns). (e) Comparison of the effect of bath application of 10 μM CGP55845 on tonic current amplitude in GAERS, stargazer and lethargic. Values were normalised to the average tonic current amplitude in the absence of CGP55845. (b), (c) and (d) * P < 0.05, ** P < 0.01 and *** P < 0.001, mutant vs. non–mutant animals under control conditions; * P < 0.05, ** P < 0.01 and *** P < 0.001, drug vs. non–drug for each strain. (e) * P < 0.05, control vs. CGP55845. For (b–e), the number of recorded neurons is as indicated.
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Related In: Results  -  Collection

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Figure 2: Aberrant GABA uptake by GAT–1 underlies enhanced tonic inhibition in GAERS, stargazer and lethargic. (a) Representative current traces in P18–21 NEC and GAERS showing the effects of block of GAT–1 alone (following bath application of 10 μM NO711, upper traces), GAT–3 alone (20 μM SNAP5114, middle traces), and GAT–1 and GAT–3 together (NO. + SNAP., lower traces), on tonic current amplitude, revealed by focal application of 100 μM GBZ (white bars). (b) Comparison of the effects of application of NO711 and SNAP5114 alone, and their co–application, on tonic current amplitude in NEC (white columns) and GAERS (black columns). (c) Comparison of the effect of NO711 and SNAP5114 alone, and their co–application, on tonic current amplitude in P19–21 stargazer (stg) mice (light grey columns) and control littermates (LIT., white columns). (d) Comparison of the effect of NO711 on tonic current amplitude in P27–30 lethargic (lh) mice (grey columns) and control littermates (LIT., white columns). (e) Comparison of the effect of bath application of 10 μM CGP55845 on tonic current amplitude in GAERS, stargazer and lethargic. Values were normalised to the average tonic current amplitude in the absence of CGP55845. (b), (c) and (d) * P < 0.05, ** P < 0.01 and *** P < 0.001, mutant vs. non–mutant animals under control conditions; * P < 0.05, ** P < 0.01 and *** P < 0.001, drug vs. non–drug for each strain. (e) * P < 0.05, control vs. CGP55845. For (b–e), the number of recorded neurons is as indicated.
Mentions: We next examined the mechanism(s) giving rise to enhanced tonic GABAA current in GAERS. Elevated GABA levels have been observed in the ventral thalamus of adult GAERS compared to NEC31, and may arise due to reduced GABA uptake32. Therefore, we tested the contribution of aberrant GABA uptake to enhanced tonic current in P18–21 GAERS compared to age–matched NEC using concentrations of GABA transporter blockers selective for GAT–1 and GAT–3 (ref. 33). In NEC, application of the GAT–1 blocker NO711 (10 μM) significantly increased tonic current compared to control conditions (P < 0.01) (Fig. 2a,b), and application of the GAT–3 blocker SNAP5114 (20 μM) increased tonic current (P < 0.001) to a greater extent than NO711, in agreement with the greater abundance of GAT–3 in the thalamus34,35. Co-application of NO711 and SNAP5114 in NEC increased tonic current (P < 0.001) to a greater extent than would be expected by simply summing the effects of NO711 and SNAP5114 alone, suggesting that block of GAT–1 causes a compensatory increase in uptake by GAT–3, and vice versa. In GAERS, application of NO711 had no effect on tonic current (P > 0.05) (Fig. 2a,b), but application of SNAP5114 caused a large increase (P < 0.001). Co–application of NO711 and SNAP5114 in GAERS significantly increased tonic current (P < 0.001), but the increase was similar to that observed following application of SNAP5114 alone, and following co–application of NO711 and SNAP5114 in NEC. Compromised GABA uptake by GAT–1 is therefore responsible for enhanced tonic current since (i) block of GAT–1 in GAERS has no effect on tonic current amplitude, (ii) block of GAT–1 in NEC increases tonic current amplitude to similar values to that seen in GAERS under control conditions, and (iii) the compensatory increase in uptake by GAT–1 following block of GAT–3 is lost in GAERS.

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