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Control of spatial memory and seizures by hippocampal mossy cells

Creative Commons 'BY-NC' version 4.0 license
Abstract

Temporal lobe epilepsy is the most common neurological disorder in adults and one of the most medically refractory. In order to develop new, more effective therapeutical approaches for TLE, we need a more complete understanding of the hippocampal structural and functional alterations underlying seizure activity and comorbid cognitive deficits. We investigated the contribution of two excitatory cell populations in the hippocampal dentate gyrus to ictal activity and spatial memory, the enigmatic hilar mossy cells and the granule cells, utilizing a combination of optogenetic, electrophysiological, and behavioral approaches in awake, behaving animals. Our main findings are: 1) decreased mossy cell activity during spontaneous, electrographic seizures permits further generalization of electrographic seizures into behavioral seizures; 2) mossy cells play a protective and anti-epileptic role in preventing seizure propagation; 3) mossy cells are necessary for encoding of spatial information, and a loss or decrease in mossy cell activity leads to memory impairments; 4) restoration of the dentate gyrus to a hyperpolarized state can robustly control seizure activity in chronic temporal lobe epilepsy, while stimulation of dentate gyrus granule cells leads to convulsive seizures. Our work has important implications for future therapeutical approaches. Our findings suggest that strategies to target the dentate gyrus microcircuitry, for example, by limiting MC loss, directly exciting surviving MCs, or inhibiting granule cells, may provide powerful treatment options for seizure control.

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