α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor Plasticity Sustains Severe, Fatal Status Epilepticus.

Adotevi N, Lewczuk E, Sun H, Joshi S, Dabrowska N, Shan S, Williamson J, Kapur J. Ann Neurol. 2020;87(1):84-96. doi: 10.1002/ana.25635. Epub 2019 Nov 20.

Generalized convulsive status epilepticus is associated with high mortality. We tested whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor plasticity plays a role in sustaining seizures, seizure generalization, and mortality observed during focal onset status epilepticus. We also determined whether modified AMPA receptors generated during status epilepticus could be targeted with a drug.

Electrically induced status epilepticus was characterized by electroencephalogram and behavior in GluA1 knockout mice and in transgenic mice with selective knockdown of the GluA1 subunit in hippocampal principal neurons. Excitatory and inhibitory synaptic transmission in CA1 neurons was studied using patch clamp electrophysiology. The dose-response of N, N, H,-trimethyl-5-([tricyclo(3.3.1.13,7)dec-1-ylmethyl]amino)-1-pentanaminiumbromide hydrobromide (IEM-1460), a calcium-permeable AMPA receptor antagonist, was determined.

Global removal of the GluA1 subunit did not affect seizure susceptibility; however, it reduced susceptibility to status epilepticus. GluA1 subunit knockout also reduced mortality, severity, and duration of status epilepticus. Absence of the GluA1 subunit prevented enhancement of glutamatergic synaptic transmission associated with status epilepticus; however, γ-aminobutyric acidergic synaptic inhibition was compromised. Selective removal of the GluA1 subunit from hippocampal principal neurons also reduced mortality, severity, and duration of status epilepticus. IEM-1460 rapidly terminated status epilepticus in a dose-dependent manner.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor plasticity mediated by the GluA1 subunit plays a critical role in sustaining and amplifying seizure activity and contributes to mortality. Calcium-permeable AMPA receptors modified during status epilepticus can be inhibited to terminate status epilepticus.

Excitatory GABAergic Signalling Is Associated With Benzodiazepine Resistance in Status Epilepticus

Burman RJ, Selfe JS, Lee JH, van den Berg M, Calin A, Codadu NK, Wright R, Newey SE, Parrish RR, Katz AA, Wilmshurst JM, Akerman CJ, Trevelyan AJ, Raimondo JV. Brain. 2019;142(11):3482-3501. doi:10.1093/brain/awz283.

Status epilepticus is defined as a state of unrelenting seizure activity. Generalized convulsive status epilepticus is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl⁻) permeable GABAA receptors, are indicated as first-line treatment, but this is ineffective in many cases. We found that 48% of children presenting with status epilepticus were unresponsive to benzodiazepine treatment, and critically, that the duration of status epilepticus at the time of treatment is an important predictor of nonresponsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic and acute brain slices. Removing Mg²⁺ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical electroencephalogram recordings of status epilepticus. We found that diazepam loses its antiseizure efficacy and conversely exacerbates epileptiform activity during this stage of status …