Unblock the Block! Preventing Inhibitory Failure to Maintain Inhibitory Restraint.

Abstract

Disrupting Epileptiform Activity by Preventing Parvalbumin Interneuron Depolarization Block Călin A, Ilie AS, Akerman CJ. J Neurosci. 2021;41(45):9452-9465. doi:10.1523/JNEUROSCI.1002-20.2021. Epub 2021 Oct 5.Inhibitory synaptic mechanisms oppose epileptic network activity in the brain. The breakdown in this inhibitory restraint and propagation of seizure activity has been linked to the overwhelming of feedforward inhibition, which is provided in large part by parvalbumin-expressing (PV) interneurons in the cortex. The underlying cellular processes therefore represent potential targets for understanding and preventing the propagation of seizure activity. Here we use an optogenetic strategy to test the hypothesis that depolarization block in PV interneurons is a significant factor during the loss of inhibitory restraint. Depolarization block results from the inactivation of voltage-gated sodium channels and leads to impaired action potential firing. We used focal NMDA stimulation to elicit reproducible epileptiform discharges in hippocampal organotypic brain slices from male and female mice and combined this with targeted recordings from defined neuronal populations. Simultaneous patch-clamp recordings from PV interneurons and pyramidal neurons revealed epileptiform activity that was associated with an overwhelming of inhibitory synaptic mechanisms and the emergence of a partial, and then complete, depolarization block in PV interneurons. To counteract this depolarization block, we developed protocols for eliciting pulsed membrane hyperpolarization via the inhibitory opsin, archaerhodopsin. This optical approach was effective in counteracting cumulative inactivation of voltage-gated channels, maintaining PV interneuron action potential firing properties during the inhibitory restraint period, and reducing the probability of initiating epileptiform activity. These experiments support the idea that depolarization block is a point of weakness in feedforward inhibitory synaptic mechanisms and represents a target for preventing the initiation and spread of seizure activity.