Tonic GABAA Receptor–Mediated Signaling in Epilepsy

Walker, Matthew; Kullmann, Dimitri M.

doi:10.1093/med/9780199746545.003.0009

Cited by 25 publications

(29 citation statements)

References 82 publications

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“…Cope et al showed that GABA A ‐mediated tonic inhibition is increased in thalamocortical neurons in GAT‐1 knockout mice. Increased GABA A ‐mediated tonic inhibition can lead to neuronal hyperpolarization and burst pattern firing in thalamocortical neurons, which can promote the generation of spike‐wave discharges . Similarly, prolonged activation of GABA B receptors is known to stimulate low voltage‐activated (T‐type) Ca 2+ channels, which can cause recurrent excitation within the thalamocortical system through successive Na + spikes .…”

Section: Discussionmentioning

confidence: 99%

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

et al. 2018

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Previous reports have identified SLC6A1 variants in patients with generalized epilepsies, such as myoclonic-atonic epilepsy and childhood absence epilepsy. However, to date, none of the identified SLC6A1 variants has been functionally tested for an effect on GAT-1 transporter activity. The purpose of this study was to determine the incidence of SLC6A1 variants in 460 unselected epilepsy patients and to evaluate the impact of the identified variants on γ-aminobutyric acid (GABA)transport. Targeted resequencing was used to screen 460 unselected epilepsy patients for variants in SLC6A1. Five missense variants, one in-frame deletion, one nonsense variant, and one intronic splice-site variant were identified, representing a 1.7% diagnostic yield. Using a [ H]-GABA transport assay, the seven identified exonic variants were found to reduce GABA transport activity. A minigene splicing assay revealed that the splice-site variant disrupted canonical splicing of exon 9 in the mRNA transcript, leading to premature protein truncation. These findings demonstrate that SLC6A1 is an important contributor to childhood epilepsy and that reduced GAT-1 function is a common consequence of epilepsy-causing SLC6A1 variants.

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Section: Discussionmentioning

confidence: 99%

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

et al. 2018

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“…The perception of δ‐containing GABA A receptors as therapeutic targets for retigabine leads to the pathophysiology of such receptors in epilepsy. In various models of temporal lobe epilepsy, δ subunit expression and functions of extrasynaptic GABA A receptors undergo complex changes . Loss of neurosteroids that activate δ‐containing GABA A receptors increases seizure frequency, whereas overexpression and activation of extrasynaptic GABA A receptors reduces seizure‐like activity in vitro and in vivo, respectively .…”

Section: Discussionmentioning

confidence: 99%

“…This, however, does not hold true for all types of seizures. Enhanced activity of extrasynaptic GABA A receptors in thalamocortical neurons is a common pathophysiologic mechanism in several models of absence epilepsy, and absence seizures are exacerbated by drugs that activate δ‐containing GABA A receptors . Retigabine has been found to be effective in virtually all types of seizure models, with the notable exception of absence seizures, even though Kv7 channels are highly expressed in the thalamus .…”

Section: Discussionmentioning

confidence: 99%

The anticonvulsant retigabine is a subtype selective modulator of GABA_A receptors

et al. 2015

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SummaryObjectiveWithin its range of therapeutic plasma concentrations, the anticonvulsant retigabine (ezogabine) is believed to selectively act on Kv7 channels. Here, the contribution of specific γ‐aminobutyric acid (GABA)A receptor subtypes to the antiseizure effects of retigabine was investigated.MethodsUsing patch‐clamp recordings, seizure‐like activity, tonic currents, and GABA‐induced currents in hippocampal neurons were tested for their sensitivity toward retigabine, as were recombinant GABA A receptors expressed in tsA 201 cells.ResultsRetigabine reduced seizure‐like activity elicited by low Mg2+ in a concentration‐dependent manner with half maximal inhibition at 1 μm. Seizure‐like activity triggered by blocking either Kv7 channels or GABA A receptors was equally reduced by retigabine, but when these channels/receptors were blocked simultaneously, the inhibition was lost. Retigabine (10 μm) enhanced bicuculline‐sensitive tonic currents in hippocampal neurons, but failed to affect GABA‐evoked currents. However, when receptors involved in phasic GABAergic inhibition were blocked by penicillin, retigabine did enhance GABA‐evoked currents. In tsA 201 cells expressing various combinations of GABA A receptor subunits, 10 μm retigabine enhanced currents through α1β2δ, α4β2δ, α4β3δ, and α6β2δ receptors, but left currents through α1β2γ2S, α4β3γ2S, α5β3γ2S, and α6β2γ2S receptors unaltered. With αβ receptors, retigabine diminished currents through α1β2 and α4β3, but increased currents through α6β2 receptors. The enhancement of currents through α1β2δ receptors by retigabine was concentration dependent and became significant at 1 μm.SignificanceThese results demonstrate that retigabine is a subtype selective modulator of GABA A receptors with preference for extrasynaptic δ‐containing receptors; this property may contribute to its broad antiepileptic effectiveness and explain its lack of effect on absence seizures.

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“…Indeed, the functional difference between mGAT1 and mGAT3/4 prompts a refinement of therapeutic targets for drugs acting on the GABA uptake systems. For example, the anti-epileptic drug, tiagabine, a mGAT1 blocker, increases GABA spillover, and can affect the time course of IPSCs (Walker and Kullmann, 2012). Because IPSCs are involved in synaptic computations, tiagabine can potentially have unwanted effects on synaptic network operation.…”

Section: Discussionmentioning

confidence: 99%

Different transporter systems regulate extracellular GABA from vesicular and non-vesicular sources

Song¹,

Volynski²,

Brenner³

et al. 2013

Front. Cell. Neurosci.

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Tonic GABA type A (GABAA) conductance is a key factor regulating neuronal excitability and computation in neuronal networks. The magnitude of the tonic GABAA conductance depends on the concentration of ambient GABA originating from vesicular and non-vesicular sources and is tightly regulated by GABA uptake. Here we show that the transport system regulating ambient GABA responsible for tonic GABAA conductances in hippocampal CA1 interneurons depends on its source. In mice, GABA from vesicular sources is regulated by mouse GABA transporter 1 (mGAT1), while that from non-vesicular sources by mouse GABA transporters 3/4 (mGAT3/4). This finding suggests that the two transporter systems do not just provide backup for each other, but regulate distinct signaling pathways. This allows individual tuning of the two signaling systems and indicates that drugs designed to act at specific transporters will have distinct therapeutic actions.

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Tonic GABAA Receptor–Mediated Signaling in Epilepsy

Cited by 25 publications

References 82 publications

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

The anticonvulsant retigabine is a subtype selective modulator of GABA_A receptors

Different transporter systems regulate extracellular GABA from vesicular and non-vesicular sources

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Tonic GABAA Receptor–Mediated Signaling in Epilepsy

Cited by 25 publications

References 82 publications

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

The anticonvulsant retigabine is a subtype selective modulator of GABAA receptors

Different transporter systems regulate extracellular GABA from vesicular and non-vesicular sources

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The anticonvulsant retigabine is a subtype selective modulator of GABA_A receptors