Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release

Yuanming Wu; Wengang Wang; George B Richerson

doi:10.1152/jn.00856.2002

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Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release

Journal article

Peer reviewed

Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release

Yuanming Wu, Wengang Wang and George B Richerson

Journal of neurophysiology, Vol.89(4), pp.2021-2034

04/2003

DOI: 10.1152/jn.00856.2002

PMID: 12612025

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Abstract

Two forms of GABAergic inhibition coexist: fast synaptic neurotransmission and tonic activation of GABA receptors due to ambient GABA. The mechanisms regulating ambient GABA have not been well defined. Here we examined the role of the GABA transporter in the increase in ambient [GABA] induced by the anticonvulsant vigabatrin. Pretreatment of cultured rat hippocampal neurons with vigabatrin (100 microM) for 2-5 days led to a large increase in ambient [GABA] that was measured as the change in holding current induced by bicuculline during patch-clamp recordings. In contrast, there was a decrease in the frequency of spontaneous miniature inhibitory postsynaptic currents mIPSCs with no change in their amplitude distribution, and a decrease in the magnitude of IPSCs evoked by presynaptic stimulation during paired recordings. The increase in ambient [GABA] was not prevented by blockade of vesicular GABA release with tetanus toxin or removal of extracellular calcium. During perforated patch recordings, the increase in ambient [GABA] was prevented by blocking the GABA transporter, indicating that the GABA transporter was continuously operating in reverse and releasing GABA. In contrast, blocking the GABA transporter increased ambient [GABA] during whole cell patch-clamp recordings unless GABA and Na(+) were added to the recording electrode solution, indicating that whole cell recordings can lead to erroneous conclusions about the role of the GABA transporter in control of ambient GABA. We conclude that the equilibrium for the GABA transporter is a major determinant of ambient [GABA] and tonic GABAergic inhibition. We propose that fast GABAergic neurotransmission and tonic inhibition can be independently modified and play complementary roles in control of neuronal excitability.

Synaptic Vesicles - metabolism

Neurons - cytology

Anticonvulsants - pharmacology

Vigabatrin - pharmacology

Neurons - physiology

Membrane Proteins - metabolism

Nipecotic Acids - pharmacology

gamma-Aminobutyric Acid - pharmacokinetics

Membrane Potentials - drug effects

Sodium - pharmacology

Carrier Proteins - antagonists & inhibitors

Cells, Cultured

Rats

Tetanus Toxin - pharmacology

Hippocampus - cytology

Rats, Sprague-Dawley

Patch-Clamp Techniques

Animals

Carrier Proteins - metabolism

Organic Anion Transporters

Membrane Proteins - antagonists & inhibitors

Membrane Transport Proteins

Receptors, GABA - metabolism

GABA Plasma Membrane Transport Proteins

Neural Inhibition - drug effects

Details

Title: Subtitle: Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release
Creators: Yuanming Wu - Departments of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
Wengang Wang
George B Richerson
Resource Type: Journal article
Publication Details: Journal of neurophysiology, Vol.89(4), pp.2021-2034
Publisher: United States
DOI: 10.1152/jn.00856.2002
PMID: 12612025
ISSN: 0022-3077
eISSN: 1522-1598
Grant note: NS-06208 / NINDS NIH HHS
Language: English
Date published: 04/2003
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neurosurgery
Record Identifier: 9984020636902771

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