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The Journal of Neuroscience, August 24, 2005, 25(34):7724-7733; doi:10.1523/JNEUROSCI.4944-04.2005

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Neurobiology of Disease
Trafficking of GABA_A Receptors, Loss of Inhibition, and a Mechanism for Pharmacoresistance in Status Epilepticus

David E. Naylor, Hantao Liu, and Claude G. Wasterlain

Department of Neurology, Veterans Administration Greater Los Angeles Healthcare System and University of California, Los Angeles, Los Angeles, California 90073

During status epilepticus (SE), GABAergic mechanisms fail and seizures become self-sustaining and pharmacoresistant. During lithiumpilocarpine-induced SE, our studies of postsynaptic GABA_A receptors in dentate gyrus granule cells show a reduction in the amplitude of miniature IPSCs (mIPSCs). Anatomical studies show a reduction in the colocalization of the 2/3 and 2 subunits of GABA_A receptors with the presynaptic marker synaptophysin and an increase in the proportion of those subunits in the interior of dentate granule cells and other hippocampal neurons with SE. Unlike synaptic mIPSCs, the amplitude of extrasynaptic GABA_A tonic currents is augmented during SE. Mathematical modeling suggests that the change of mIPSCs with SE reflects a decrease in the number of functional postsynaptic GABA_A receptors. It also suggests that increases in extracellular [GABA] during SE can account for the tonic current changes and can affect postsynaptic receptor kinetics with a loss of paired-pulse inhibition. GABA exposure mimics the effects of SE on mIPSC and tonic GABA_A current amplitudes in granule cells, consistent with the model predictions. These results provide a potential mechanism for the inhibitory loss that characterizes initiation of SE and for the pharmacoresistance to benzodiazepines, as a reduction of available functional GABA_A postsynaptic receptors. Novel therapies for SE might be directed toward prevention or reversal of these losses.

Key words: GABA_A receptor trafficking; status epilepticus; epilepsy; hippocampus; math model; synaptic inhibition

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Received Dec 5, 2004; revised July 7, 2005; accepted July 12, 2005.

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