Hippocampal GABA transporter function in temporal-lobe epilepsy

During, Matthew J.; Ryder, Kathryn; Spencer, Dennis D.

doi:10.1038/376174a0

Cited by 315 publications

(169 citation statements)

References 22 publications

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“…The large increase in extracellular [GABA] after the fusion of synaptic vesicles would be expected to drive reuptake, but when extracellular [GABA] is low, nonvesicular GABA efflux commonly may occur at relatively low firing rates. Previous studies also have suggested that nonvesicular GABA efflux can be functionally important under some conditions (Schwartz, 1987;Taylor and Gordon-Weeks, 1991;During et al, 1995;Drew et al, 1997).…”

Section: Functional Role Of the Gaba Transportermentioning

confidence: 99%

“…An increased number of GABA transporters in the plasma membrane would increase the flux of GABA under the force of a constant [GABA] gradient. Conversely, within the seizure focus of human temporal lobe epilepsy patients there is evidence for a decrease in the number of functional GABA transporters (During et al, 1995), which could contribute to seizure generation or spread. It is likely that a variety of other factors could modulate GABA transporter number or alter the function of those transporters that are present.…”

Section: Anticonvulsant Mechanism Of Vigabatrinmentioning

confidence: 99%

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GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

2001

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The GABA transporter can reverse with depolarization, causing nonvesicular GABA release. However, this is thought to occur only under pathological conditions. Patch-clamp recordings were made from rat hippocampal neurons in primary cell cultures. Inhibition of GABA transaminase with the anticonvulsant ␥-vinyl GABA (vigabatrin; 0.05-100 M) resulted in a large leak current that was blocked by bicuculline (50 M). This leak current occurred in the absence of extracellular calcium and was blocked by the GABA transporter antagonist SKF-89976a (5 M). These results indicate that vigabatrin induces spontaneous GABA efflux from neighboring cells via reversal of GABA transporters, subsequently leading to the stimulation of GABA A receptors on the recorded neuron. The leak current increased slowly over 4 d of treatment with 100 M vigabatrin, at which time it reached an equivalent conductance of 9.0 Ϯ 4.9 nS. Blockade of glutamic acid decarboxylase with semicarbazide (2 mM) decreased the leak current that was induced by vigabatrin by 47%. In untreated cells, carrier-mediated GABA efflux did not occur spontaneously but was induced by an increase in [K ϩ ] o from 3 to as little as 6 mM. Vigabatrin enhanced this depolarization-evoked nonvesicular GABA release and also enhanced the heteroexchange release of GABA induced by nipecotate. Thus, the GABA transporter normally operates near its equilibrium and can be easily induced to reverse by an increase in cytosolic [GABA] or mild depolarization. We propose that this transporter-mediated nonvesicular GABA release plays an important role in neuronal inhibition under both physiological and pathophysiological conditions and is the target of some anticonvulsants.

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Section: Functional Role Of the Gaba Transportermentioning

confidence: 99%

Section: Anticonvulsant Mechanism Of Vigabatrinmentioning

confidence: 99%

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

2001

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“…Human studies indicated that GABA transporter function is reduced in epileptic hippocampi (During et al, 1995;Williamson et al, 1995). This may result from a reversed GABA transport due to membrane depolarization.…”

Section: Transporters As Pharmacological Targetsmentioning

confidence: 99%

The Family of Na⁺/Cl⁻ Neurotransmitter Transporters

Nelson

1998

Journal of Neurochemistry

344

192

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Abstract:The termination of neurotransmission is achieved by rapid uptake of the released neurotransmitter by specific high-affinity neurotransmitter transporters. Most of these transporters are encoded by a family of genes (Na~ICI transporters) having a similar membrane topography of 12 transmembrane helices. An evolutionary tree revealed fivedistinct subfamilies: y-aminobutyric acid transporters, monoamine transporters, amino acid transporters, "orphan" transporters, and the recently discovered bacterial transporters. The bacterial transporters that belong to this family may help to develop heterologous expression systems with the aim of solving the threedimensional structure of these membrane proteins. Some of the neurotransmitter transporters have been implicated as important sites for drug action. Monoamine transporters, for example, are targeted by major classes of antidepressants, psychostimulants, and antihypertensive drugs. Localization of individual transporters in specific cells and brain areas is pertinent to understanding their contribution to neurotransmission and their potential as targets for drugs. The most important questions in the field include resolving the mechanism of neurotransmitter transport, the structure of the transporters, and the interaction of each transporter in complex neurological activities.

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“…Recent evidence suggests that the GABA uptake is reduced in tissue from animals and humans with ' Author for correspondence. chronic temporal lobe epilepsy (Janjua et al, 1991;During et al, 1995). This should lead to prolonged synaptic inhibition and might reflect an adaptation to hyperexcitability.…”

Section: Introductionmentioning

confidence: 99%

Effects of γ‐aminobutyric acid (GABA) agonists and GABA uptake inhibitors on pharmacosensitive and pharmacoresistant epileptiform activity in vitro

Pfeiffer

Draguhn

Meierkord

et al. 1996

British J Pharmacology

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2 A mechanism possibly underlying the development of sustained seizure-like activity is the loss of synaptically released y-aminobutyric acid (GABA). Drugs which increase the amount of GABA available in presynaptic endings might thus be useful in the treatment of these therapeutically complicated forms of epilepsy. 3 Therefore, we studied the effects of various substances increasing GABA-mediated inhibition on early and late forms of epileptiform activity. GABA and the GABAA receptor agonist muscimol blocked both the pharmacosensitive discharges in the hippocampus and entorhinal cortex as well as the late recurrent discharges in the medial entorhinal cortex. The GABAB receptor agonist baclofen blocked the recurrent short discharges very potently, but did not consistently block seizure-like events and late recurrent discharges in the entorhinal cortex. 4 GABA uptake blockers showed a differential potency to block the various discharge patterns.Whereas nipecotic acid and P-alanine suppressed all forms of epileptiform activity albeit at high concentrations (1-5 mM), tiagabine was much more potent in blocking the hippocampal recurrent short discharges and the seizure-like events in the medial entorhinal cortex, but could not block the late recurrent discharges. 5 Our data support the idea that prolonged neuronal overactivity might result in a loss of synaptically available GABA. Selective block of uptake into glia cells or substitution of the transmitter may therefore be an efficient strategy for the treatment of severe prolonged epileptic discharges whereas block of neuronal GABA uptake fails to counteract synchronized discharges in this situation.

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Hippocampal GABA transporter function in temporal-lobe epilepsy

Cited by 315 publications

References 22 publications

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

The Family of Na⁺/Cl⁻ Neurotransmitter Transporters

Effects of γ‐aminobutyric acid (GABA) agonists and GABA uptake inhibitors on pharmacosensitive and pharmacoresistant epileptiform activity in vitro

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Hippocampal GABA transporter function in temporal-lobe epilepsy

Cited by 315 publications

References 22 publications

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

The Family of Na+/Cl− Neurotransmitter Transporters

Effects of γ‐aminobutyric acid (GABA) agonists and GABA uptake inhibitors on pharmacosensitive and pharmacoresistant epileptiform activity in vitro

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The Family of Na⁺/Cl⁻ Neurotransmitter Transporters