In the fast lane: Receptor trafficking during status epilepticus

Abstract

Status epilepticus (SE) remains a significant cause of morbidity and mortality and often is refractory to standard first‐line treatments. A rapid loss of synaptic inhibition and development of pharmacoresistance to benzodiazepines (BZDs) occurs early during SE, while NMDA and AMPA receptor antagonists remain effective treatments after BZDs have failed. Multimodal and subunit‐selective receptor trafficking within minutes to an hour of SE involves GABA‐A, NMDA, and AMPA receptors and contributes to shifts in the number and subunit composition of surface receptors with differential impacts on the physiology, pharmacology, and strength of GABAergic and glutamatergic currents at synaptic and extrasynaptic sites. During the first hour of SE, synaptic GABA‐A receptors containing γ2 subunits move to the cell interior while extrasynaptic GABA‐A receptors with δ subunits are preserved. Conversely, NMDA receptors containing N2B subunits are increased at synaptic and extrasynaptic sites, and homomeric GluA1 (“GluA2‐lacking”) calcium permeant AMPA receptor surface expression also is increased. Molecular mechanisms, largely driven by NMDA receptor or calcium permeant AMPA receptor activation early during circuit hyperactivity, regulate subunit‐specific interactions with proteins involved with synaptic scaffolding, adaptin‐AP2/clathrin‐dependent endocytosis, endoplasmic reticulum (ER) retention, and endosomal recycling. Reviewed here is how SE‐induced shifts in receptor subunit composition and surface representation increase the excitatory to inhibitory imbalance that sustains seizures and fuels excitotoxicity contributing to chronic sequela such as “spontaneous recurrent seizures” (SRS). A role for early multimodal therapy is suggested both for treatment of SE and for prevention of long‐term comorbidities.

Staged treatment response in status epilepticus: Lessons from the SENSE registry

“…During ongoing SE, changes in neurotransmission might potentially contribute to treatment resistance. In animal models, these alterations have been verified to favor the development of self‐sustaining seizures and to render ASMs with γ‐aminobutyric acid (GABA)ergic mechanisms less effective and the glutamatergic receptor system upregulated over time, leading to marked disinhibition and hyperexcitability 11 . These findings are only partially confirmed by our clinical findings: the proportion of SE cessation was significantly lower after the first two treatment steps, confirming the higher drug resistance of RSE 12 ; however, the proportion of SE cessation did not decrease significantly at further treatment steps, and no clear plateau was reached.…”

Status epilepticus: Is there a Stage 1 plus?

“…16,17,[20][21][22] Many studies both on humans and animals have highlighted a rapid loss of BDZ potency as seizures persist 9,14,15,23 ; the mechanism that explains this phenomenon is receptor trafficking during SE. 24 Receptor trafficking not only lowers the total number of plasma membrane GABA-A receptors but also leads to the relocation of BDZ-sensitive γ2 subunit receptors away from synapses and to the cell interior after prolonged SE. 16 GABA-A receptors moving away from synapses seem to be determinative for BDZ loss of response.…”

“…30 Moreover, NMDARs activation engages calcineurin and post-translational modulators that perpetuate the trafficking of GABA receptors away from synapses. 24 This consideration may prove useful in possible therapeutic synergistic combinations. Niquet et al published interesting results of a rat model of SE with different treatments: monotherapy, dual therapy, and triple therapy.…”

“…This leads to a pro‐excitatory state that is typically resistant to BDZs, and this is more evident after 30 min of SE onset, 17,19 but it starts even sooner than 10 min after SE onset 16,17,20–22 . Many studies both on humans and animals have highlighted a rapid loss of BDZ potency as seizures persist 9,14,15,23 ; the mechanism that explains this phenomenon is receptor trafficking during SE 24 . Receptor trafficking not only lowers the total number of plasma membrane GABA‐A receptors but also leads to the relocation of BDZ‐sensitive γ2 subunit receptors away from synapses and to the cell interior after prolonged SE 16 .…”

“…Receptor trafficking is not limited to GABA receptors; antagonists of N‐methyl‐D‐aspartate receptors (NMDARs) can retain therapeutic and clinical efficacy even into prolonged SE, 26–29 as NMDARs relocate in higher numbers on synapses 30 . Moreover, NMDARs activation engages calcineurin and post‐translational modulators that perpetuate the trafficking of GABA receptors away from synapses 24 …”