In vivo evaluation of the dentate gate theory in epilepsy

Key points A key mechanistic concept in epilepsy is the dentate gate hypothesis, which argues that the dentate gyrus protects hippocampal circuits from overexcitation and that a breakdown of this gate leads to epilepsy. Direct in vivo evidence for the dentate gate hypothesis is lacking and it is therefore unclear whether interventions selectively targeting the dentate gyrus would inhibit seizures. We demonstrate that on‐demand optogenetic restoration of the dentate gate through selective inhibition of granule cells is sufficient to inhibit spontaneous seizures in a mouse model of temporal lobe epilepsy. By contrast, activation of granule cells worsens spontaneous seizures and can even induce acute seizures in non‐epileptic animals. These data provide direct evidence for the dentate gate hypothesis, indicate that the dentate gyrus is indeed a critical node in temporal lobe seizure circuitry, and illustrate that the dentate gyrus can be an effective target for seizure inhibition. 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.