Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures

Jin Shun Qi, Jun Yao, Cheng Fang, Bernhard Luscher, Gong Chen

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Deficits in GABAergic inhibitory transmission are a hallmark of temporal lobe epilepsy and have been replicated in animal and tissue culture models of epilepsy. GABAergic inhibition comprises phasic and tonic inhibition that is mediated by synaptic and extrasynaptic GABAA receptors, respectively. We have recently demonstrated that chronic stimulation with cyclothiazide (CTZ) or kainic acid (KA) induces robust epileptiform activity in hippocampal neurons both in vtro and in vivo. Here, we report a downregulation of tonic GABA inhibition after chronic epileptogenic stimulation of rat hippocampal cultures. Chronic pretreatment of hippocampal neurons with CTZ or KA resulted in a marked reduction in GABAergic inhibition, as shown by a significant decrease in whole-cell GABA currents and in the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Interestingly, synaptically localized GABAA receptors remained relatively stable, as evidenced by the unaltered amplitude of mIPSCs, as well as the unchanged punctate immunoreactivity of γ2 subunit-containing postsynaptic GABAA receptors. In contrast, tonic GABA currents, assessed either by a GABAA receptor antagonist bicuculline or a selective extrasynaptic GABAA receptor agonist THIP, were significantly reduced following epileptogenic stimulation. These results reveal a novel form of neural plasticity, that epileptogenic stimulation can selectively downregulate extrasynaptic GABAA receptors while leaving synaptic GABAA receptors unchanged. Thus, in addition to synaptic alteration of GABAergic transmission, regulation of tonic inhibition may also play an important role during epileptogenesis.

Original languageEnglish (US)
Pages (from-to)579-590
Number of pages12
JournalJournal of Physiology
Volume577
Issue number2
DOIs
StatePublished - Dec 1 2006

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GABA-A Receptors
gamma-Aminobutyric Acid
Down-Regulation
Inhibitory Postsynaptic Potentials
Kainic Acid
GABA-A Receptor Agonists
GABA-A Receptor Antagonists
Neurons
Neurotransmitter Receptor
Neuronal Plasticity
Bicuculline
Temporal Lobe Epilepsy
Epilepsy
cyclothiazide

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

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title = "Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures",
abstract = "Deficits in GABAergic inhibitory transmission are a hallmark of temporal lobe epilepsy and have been replicated in animal and tissue culture models of epilepsy. GABAergic inhibition comprises phasic and tonic inhibition that is mediated by synaptic and extrasynaptic GABAA receptors, respectively. We have recently demonstrated that chronic stimulation with cyclothiazide (CTZ) or kainic acid (KA) induces robust epileptiform activity in hippocampal neurons both in vtro and in vivo. Here, we report a downregulation of tonic GABA inhibition after chronic epileptogenic stimulation of rat hippocampal cultures. Chronic pretreatment of hippocampal neurons with CTZ or KA resulted in a marked reduction in GABAergic inhibition, as shown by a significant decrease in whole-cell GABA currents and in the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Interestingly, synaptically localized GABAA receptors remained relatively stable, as evidenced by the unaltered amplitude of mIPSCs, as well as the unchanged punctate immunoreactivity of γ2 subunit-containing postsynaptic GABAA receptors. In contrast, tonic GABA currents, assessed either by a GABAA receptor antagonist bicuculline or a selective extrasynaptic GABAA receptor agonist THIP, were significantly reduced following epileptogenic stimulation. These results reveal a novel form of neural plasticity, that epileptogenic stimulation can selectively downregulate extrasynaptic GABAA receptors while leaving synaptic GABAA receptors unchanged. Thus, in addition to synaptic alteration of GABAergic transmission, regulation of tonic inhibition may also play an important role during epileptogenesis.",
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Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures. / Qi, Jin Shun; Yao, Jun; Fang, Cheng; Luscher, Bernhard; Chen, Gong.

In: Journal of Physiology, Vol. 577, No. 2, 01.12.2006, p. 579-590.

Research output: Contribution to journalArticle

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