Editor’s Pick: Towards causality for mechanisms of seizures in epilepsy

Reviewing Editor William Stacey, Ph.D. selected this paper and explains why he considers it noteworthy.

A common theory of epilepsy is that seizures result from disruptions to the excitatory/inhibitory balance. While this is a logical hypothesis, there are many other factors that can also play a role and it is difficult to isolate “inhibitory drive” experimentally to prove causality and characterize the mechanisms. In this work, Dusing and colleagues expand upon prior work from other labs to take a large step towards that goal.

The authors performed two separate experiments to isolate and remove inhibition in the hippocampus. First, they induced bilateral deletion of Vgat-expressing interneurons in dorsal and ventral hippocampus with diphtheria toxin in mice. Second, they targeted the same cells transiently using DREADDS in a different group of mice. Both methods led to a global inactivation of the interneurons: permanently in the Vgat ablation and transiently for the DREADDS. They monitored epileptiform activity with continuous EEG and found that, surprisingly, even with bilateral ablation of roughly half of hippocampal interneurons a dramatic increase in seizures was evident in the following week though this was largely resolved in the following weeks.

These findings have two principal conclusions. First, they demonstrate that isolated silencing of interneurons increases seizures. While important to prove, those findings are expected. The second conclusion is unexpected: seizures were not nearly as severe nor long-lasting as expected, implying robust homeostasis through as-yet unidentified mechanisms. These results lead to several intriguing questions for future research.

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Synaptotagmin-7 Counteracts Short-Term Depression during Phasic Dopamine Release
Joseph J. Lebowitz, Sarah A. Kissiwaa, Kim A. Engeln, Anna M. Bowman, John T. Williams, and Skyler L. Jackman