TY - JOUR T1 - Trafficking of GABA<sub>A</sub> Receptors, Loss of Inhibition, and a Mechanism for Pharmacoresistance in Status Epilepticus JF - The Journal of Neuroscience JO - J. Neurosci. SP - 7724 LP - 7733 DO - 10.1523/JNEUROSCI.4944-04.2005 VL - 25 IS - 34 AU - David E. Naylor AU - Hantao Liu AU - Claude G. Wasterlain Y1 - 2005/08/24 UR - http://www.jneurosci.org/content/25/34/7724.abstract N2 - 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 β2/β3 and γ2 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. ER -