Editors' ChoiceEpilepsy

Not just uninhibited: Interneurons and seizure onset

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Science Translational Medicine  21 Nov 2018:
Vol. 10, Issue 468, eaav9143
DOI: 10.1126/scitranslmed.aav9143

Abstract

Optogenetic study in vivo demonstrates that different types of interneurons show consistently elevated but distinct firing patterns in the period preceding seizure onset in a rodent model of epilepsy.

What triggers an epileptic seizure? One theory is that the delicate balance between excitation and inhibition in the brain is disrupted, leading to runaway excitation and hence, seizures. Many researchers have tried to address this question by studying what is happening in the brain during the time just before a seizure strikes, known as the preictal period. In particular, a prevalent idea has been that seizures may result from a failure of inhibitory GABAergic interneurons to keep excitation in check. However, this remains controversial, as studies have shown various preictal interneuron firing patterns. Multiple interneuron subtypes have been recognized in the brain, exhibiting different behavior in physiological and pathological conditions; however, distinguishing between different interneuron populations in vivo is challenging.

Now, an elegant study by Miri et al. has used optogenetics coupled with specific conditional Cre mouse lines to allow identification in vivo of two interneuron types, parvalbumin (PV)– and somatostatin (SST)–expressing interneurons, as well as putative excitatory neurons in the hippocampus in a rodent model of epilepsy. The researchers inserted a light fiber into the hippocampus of anesthetized mice to activate the different cell types expressing channelrhodopsin and a tetrode electrode to record individual neuronal firing. Then, theyadministered a drug, pentylenetetrazol (PTZ), which induces seizures. In this way, they were able to monitor the firing behavior of different cell types at different points before the onset of seizure, as well as during the seizure itself. Surprisingly, all neurons showed elevations in firing during this preictal period, with the PV interneurons showing a dramatic increase in firing frequency just before seizure onset. Compellingly, they replicated their findings in awake, behaving mice and with a different chemoconvulsant. Taking further advantage of their optogenetic approach, they were able to demonstrate that both interneuron types were still able to inhibit firing in excitatory neurons at all points before and during seizure. Instead of a failure in inhibition, they found complex and cell type–specific changes in firing behavior, implying that the issue is more one of how different interneurons operate within the hippocampal network.

A more detailed description of network dynamics and cellular responses during the preictal and ictal periods will likely reveal more, and there is a need to translate findings from such model systems into patients. Yet this work strengthens the concept that it is not simply a failure of inhibition that triggers seizures, but a far more complex interplay between different cell types.

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