Trafficking of GABA_AReceptors, Loss of Inhibition, and a Mechanism for Pharmacoresistance in Status Epilepticus

Abstract

During status epilepticus (SE), GABAergic mechanisms fail and seizures become self-sustaining and pharmacoresistant. During lithiumpilocarpine-induced SE, our studies of postsynaptic GABAAreceptors 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 GABAAreceptors 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 GABAAtonic currents is augmented during SE. Mathematical modeling suggests that the change of mIPSCs with SE reflects a decrease in the number of functional postsynaptic GABAAreceptors. 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 GABAAcurrent 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 GABAApostsynaptic receptors. Novel therapies for SE might be directed toward prevention or reversal of these losses.

Ubiquitin-dependent lysosomal targeting of GABA A receptors regulates neuronal inhibition

“…Modified membrane trafficking of GABA A Rs is strongly implicated in a reduction in the number of surface and synaptic GABA A Rs, which contributes to the loss of inhibition in status epilepticus (6,(37)(38)(39) and ischemic brain injury (4,8), but the mechanisms have remained unclear. Here, we demonstrate that although anoxic insult reduces the number of wild type GFPtagged synaptic GABA A Rs, the synaptic expression of GABA A Rs incorporating GFP ␥2 K7R subunits (and hence no longer ubiquitinated) remained unaffected.…”

“…Moreover, in a number of neuropathologies, including status epilepticus and in vitro and in vivo models of cerebral ischemia, the rapid downmodulation of synaptic GABA A Rs has been reported to contribute to pathological disinhibition, excitotoxicity, and cell death (4)(5)(6)(7)(8). However, the molecular mechanisms and signaling pathways that regulate GABA A R trafficking, under normal or pathological conditions, remain unclear.…”

Nonconvulsive status epilepticus: a diagnostic and therapeutic challenge in the intensive care setting

“…Continuous administration of iv barbiturates commonly causes pressorrequiring arterial hypotension, severe gastrioparesis and immunosuppression facilitating infections and sepsis [Ropper, 2003]. Progressive erosion of inhibition due to depletion of postsynaptic GABA receptors with ongoing epileptic activity [Naylor et al 2005] may result in loss of efficacy of anaesthetics such as propofol, barbiturates and midazolam. Recurrence of seizure activity after tapering of anaesthetics has been described in more than 50% of cases [Claassen et al 2001], and for this difficult-to-treat and prognostically poor variant we suggest the term 'malignant' status epilepticus [Holtkamp et al 2005a].…”

First‐in‐man allopregnanolone use in super‐refractory status epilepticus

“…When prolonged therapeutic coma is used, tachyphylaxis to anesthetics that act via GABA A receptors, such as barbiturates and benzodiazepines, is frequently observed. Both continuous seizure activity and GABAergic drugs cause synaptic GABA A receptor internalization and desensitization leading to cortical hyperexcitability 6, 7, 8. Extrasynaptic GABA A receptors are not internalized and could be targeted during treatment of SRSE 9.…”