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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 GABAA 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 GABAA 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 GABAA 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 GABAA 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 GABAA 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 GABAA 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 GABAA postsynaptic receptors. Novel therapies for SE might be directed toward prevention or reversal of these losses.
Key words: GABAA receptor trafficking; status epilepticus; epilepsy; hippocampus; math model; synaptic inhibition
Received Dec 5, 2004;
revised July 7, 2005;
accepted July 12, 2005.
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