A Novel Excitatory and Epileptogenic Effect of Dentate Gyrus Mossy Cells in a Mouse Model of Epilepsy

Abstract

The sparse activity of hippocampal dentate gyrus (DG) granule cells (GCs) is thought to be critical for cognition and behavior, whereas excessive DG activity is thought to 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 direct innervation of GCs or indirectly through GABAergic neurons. Here we test the hypothesis that MC excitation of GCs is normally weak, but under special conditions, MC excitation of GCs is robust. Our results show that selectively inhibiting MCs during severe seizures reduced the severity of those seizures, hippocampal injury, and chronic epilepsy. Mechanistic in vitro studies using optogenetics further demonstrated the underappreciated ability of MC axons to robustly excite GCs under specific conditions. These results demonstrate a conditional excitatory effect of MCs in the DG