The Gate and the Source? the Dentate Gyrus Takes Central Stage in Temporal Lobe Epilepsy

Abstract

CommentaryIn healthy tissue, dentate granule cells respond to entorhinal input with very sparse activation, limiting the flow of excitation through the hippocampal circuit. This 'gating' function of the dentate can be impaired in temporal lobe epilepsy, such that even normal input from the entorhinal cortex might produce greater levels of activity in the dentate. This greater dentate output would then feed through the circuit and be proictogenic. A recent study by Norwood and colleagues adds an interesting twist to the classic dentate gate hypothesis of temporal lobe epilepsy; their findings reported in Meyer et al. suggest that entorhinal input may not be necessary for ictogenesis.Meyer et al. used the perforant path stimulation model to induce temporal lobe epilepsy in rats. In this model, after 2 priming days of 30-min stimulation, the perforant path is stimulated for 8 hours in awake animals at a subconvulsive level [1]. This results in immediate hippocampal cell damage and loss, and the appearance of spontaneous dentate discharges. Spontaneous behavioral seizures arise in this model 2 to 3 weeks after the 8-hour performant path stimulation insult.The spontaneous discharges in the dentate, which appear immediately after the 8 hours of perforant path stimulation are remarkably similar to potentials directly evoked by stimulation of the entorhinal input to the dentate. This similarity caused Norwood and colleagues to previously note "the first spontaneous potentials closely resembled what would be expected from the granule cell layer if the seizures originated in the entorhinal cortex" and, holding with the classic view of the dentate gate hypothesis, "the available evidence is consistent with spontaneous 'hippocampal-onset' granule cell seizure discharges that may have been preceded and driven by spontaneous and synchronized entorhinal cortex discharges" (1). Thus, a reasonable interpretation was that the spontaneous discharges in the dentate were driven by the entorhinal cortex. A similar scenario was suggested for the spontaneous behavioral seizures that later develop in the model: "We hypothesize that the seizures in this model begin outside the hippocampus… and that only when the originating seizure activity recruits epileptiform discharges from disinhibited dentate granule cells do clinical seizures occur" (1). Previous findings were thus consistent with the hypothesis that input from the entorhinal cortex ultimately drove seizure expression. And so, in Meyer et al., they did a simple test-immediately after perforant path stimulation, they physically cut off the entorhinal input to the dentate. The effect? Nothing. Removing Entorhinal Cortex Input to the Dentate Gyrus Does not Impede Low Frequency Oscillations, an EEGbiomarker of Hippocampal Epileptogenesis.Meyer M, Kienzler-Norwood F, Bauer S, Rosenow F, Norwood BA. Sci Rep 2016;6:25660.Following prolonged perforant pathway stimulation (PPS) in rats, a seizure-free "latent period" is observed that lasts around 3 weeks. During this time, aberrant neurona...

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“…As regional changes in βArr2 and CB1R could be missed when studying the whole hippocampus, we analyzed whether putative differences in the expression levels of βArr2 and CB1R that were not visible by Western blot could be revealed by local examination of the hippocampal dentate gyrus of female rats (representative figures, Figures 5A,B ; Supplementary Table 5 ). This region was chosen as it is crucial in the control of excitability arising from other brain areas (e.g., entorhinal cortex), though seizures may be generated regardless of external inputs (Krook-Magnuson, 2017 ). In the hilus of the dentate gyrus excitatory mossy cells express CB1R (Krook-Magnuson et al, 2015 ; Sugaya et al, 2016 ; Jensen et al, 2021 ).…”

Specificity, Versatility, and Continual Development: The Power of Optogenetics for Epilepsy Research

“…The dentate gate hypothesis posits that, in TLE, there is a breakdown of this gating function, granule cells become relatively over-active, and too much excitation flows through the hippocampal circuit. Whether the excitatory drive pushing seizures arrives from the entorhinal cortex, some other outside source, or from the dentate itself is currently under consideration (Meyer et al, 2016 ; Krook-Magnuson, 2017 ). Regardless of the source of the excitatory drive, fundamental to the dentate gate hypothesis is that granule cells show heightened activity levels.…”