In vivo evaluation of the dentate gate theory in epilepsy

Abstract

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.