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J Physiol Volume 577, Number 2, 579-590, December 1, 2006 DOI: 10.1113/jphysiol.2006.113134
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NEUROSCIENCE

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

Jin-shun Qi1,3, Jun Yao1, Cheng Fang1, Bernhard Luscher1,2 and Gong Chen1

Departments of
1 Biology
2 Biochemistry and Molecular Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
3 Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, P. R. China

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 vitro 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 {gamma}2 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.

(Received 15 May 2006; accepted after revision 20 September 2006; first published online 21 September 2006)
Corresponding author G. Chen: Department of Biology, 201 Life Sciences Building, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.  Email: gongchen{at}psu.edu




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