Fifty years of research on status epilepticus: Seizures use hippocampal memory circuits to generate status epilepticus and disrupt brain development.

This is a review of my laboratory's interest in status epilepticus (SE), which spanned five decades. It started with a study of the role of brain mRNAs in memory, and with the use of electroconvulsive seizures to disrupt recently acquired memories. This led to biochemical studies of brain metabolism during seizures, and to the serendipitous development of the first model of self-sustaining SE. The profound inhibition of brain protein synthesis by seizures had implications for brain development, and we showed that severe seizures and SE in the absence of hypoxemia and other metabolic complications can disrupt brain and behavioral development, a concept that was not widely accepted at that time. We also showed that many experimental models of SE can cause neuronal death in the immature brain, even at very young ages. Our studies of self-sustaining SE showed that the transition from single seizures to SE is accompanied by internalization and transient inactivation of synaptic GABAA receptors, while extrasynaptic GABAA receptors are untouched. At the same time, NMDA and AMPA receptors move to the synaptic membrane, creating a "perfect storm" combining failure of inhibition and runaway excitation. Major maladaptive changes in protein kinases and neuropeptides, particularly galanin and tachykinins, also contribute to the maintenance of SE. The therapeutic implications of these results are that our current practice to start the treatment of SE with benzodiazepine monotherapy leaves the changes in glutamate receptors untreated and that sequential use of drugs gives seizures more time to aggravate changes in receptor trafficking. In experimental SE, we showed that drug combinations based on the receptor trafficking hypothesis are far superior to monotherapy in stopping SE late in its course. Combinations that include an NMDA receptor blocker such as ketamine are much better than combinations that follow current evidence-based guidelines, and simultaneous delivery of the drugs is far more effective than sequential delivery of the same drugs at the same dose. This paper was presented as a Keynote Lecture at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.