In vivo evaluation of the dentate gate theory in epilepsy

Esther Krook-Magnuson, Caren Armstrong, Anh Bui, Sean Lew, Mikko Oijala, Ivan Soltesz

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The dentate gyrus is a region subject to intense study in epilepsy because of its posited role as a 'gate', acting to inhibit overexcitation in the hippocampal circuitry through its unique synaptic, cellular and network properties that result in relatively low excitability. Numerous changes predicted to produce dentate hyperexcitability are seen in epileptic patients and animal models. However, recent findings question whether changes are causative or reactive, as well as the pathophysiological relevance of the dentate in epilepsy. Critically, direct in vivo modulation of dentate 'gate' function during spontaneous seizure activity has not been explored. Therefore, using a mouse model of temporal lobe epilepsy with hippocampal sclerosis, a closed-loop system and selective optogenetic manipulation of granule cells during seizures, we directly tested the dentate 'gate' hypothesis in vivo. Consistent with the dentate gate theory, optogenetic gate restoration through granule cell hyperpolarization efficiently stopped spontaneous seizures. By contrast, optogenetic activation of granule cells exacerbated spontaneous seizures. Furthermore, activating granule cells in non-epileptic animals evoked acute seizures of increasing severity. These data indicate that the dentate gyrus is a critical node in the temporal lobe seizure network, and provide the first in vivo support for the dentate 'gate' hypothesis.

Original languageEnglish (US)
Pages (from-to)2379-2388
Number of pages10
JournalJournal of Physiology
Issue number10
StatePublished - May 15 2015

Bibliographical note

Funding Information:
This work was supported by Citizens United for Research in Epilepsy (CURE) Taking Flight Award (to EK‐M), a US National Institutes of Health grant F31NS086429 (to AB), the Epilepsy Foundation (to CA) and a US National Institutes of Health grant NS074432 (to IS).

Funding Information:
We thank Cecilia Lozoya, Rose Zhu, Judit Vargane, Chris Krook‐Magnuson and Dhrumil Vyas for providing technical support. This work was made possible, in part, through access to the confocal facility of the Optical Biology Shared Resource of the Cancer Centre Support Grant (CA‐62203) at the University of California, Irvine.

Publisher Copyright:
© 2015 The Physiological Society.


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