Cell Reports
Volume 29, Issue 9, 26 November 2019, Pages 2875-2889.e6
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Article
An Excitatory and Epileptogenic Effect of Dentate Gyrus Mossy Cells in a Mouse Model of Epilepsy

https://doi.org/10.1016/j.celrep.2019.10.100Get rights and content
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Highlights

  • MC excitation of GCs increases during pathological conditions that cause epilepsy

  • Pathological excitation of GCs by MCs leads to excitotoxicity of the targets of GCs

  • GABA and NMDA receptors regulate pathological excitation of GCs by MCs

  • By increasing excitotoxicity early in epileptogenesis, MCs contribute to epilepsy

Summary

The sparse activity of hippocampal dentate gyrus (DG) granule cells (GCs) is thought to be critical for cognition and behavior, whereas excessive DG activity may contribute to disorders such as temporal lobe epilepsy (TLE). Glutamatergic mossy cells (MCs) of the DG are potentially critical to normal and pathological functions of the DG because they can regulate GC activity through innervation of GCs or indirectly through GABAergic neurons. Here, we test the hypothesis that MC excitation of GCs is normally weak, but under pathological conditions, MC excitation of GCs is dramatically strengthened. We show that selectively inhibiting MCs during severe seizures reduced manifestations of those seizures, hippocampal injury, and chronic epilepsy. In contrast, selectively activating MCs was pro-convulsant. Mechanistic in vitro studies using optogenetics further demonstrated the unanticipated ability of MC axons to excite GCs under pathological conditions. These results demonstrate an excitatory and epileptogenic effect of MCs in the DG.

Keywords

mossy cell
hilus
epilepsy
seizure
hippocampus
EEG
DREADDs
pilocarpine
dentate gyrus
optogenetics

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