Hilar mossy cells control structural and functional organization in the dentate gyrus

Hilar mossy cells in the dentate gyrus project widely throughout the hippocampus, broadly contributing to circuit function. Their loss in disease is associated with local functional and structural rearrangements, including retrograde granule cell axon sprouting, aberrant neurogenesis, and disinhibition. To examine how mossy cell loss contributes to these circuit rearrangements, we ablated or silenced hilar mossy cells using viral approaches in transgenic (Crlr-Cre) mice. Both mossy cell ablation and silencing dramatically altered dentate gyrus structure and function, as assessed using immunohistochemical, viral labeling, electrophysiology, and anatomical methods. Both manipulations accelerated the maturation of adult-born neurons, but did not alter neuroblast proliferation or cause granule cell axon sprouting. However, mossy cell ablation, but not silencing, caused collapse of the inner molecular layer accompanied by proximal translocation of middle molecular layer inputs. In both cases, granule cell activity measured by cFos labeling and seizure susceptibility were unchanged after mossy cell loss, indicating functional compensation for the altered network organization. Our results highlight how mossy cells influence dentate gyrus organization and adult neurogenesis but also demonstrate the resilience of the hippocampal circuit to structural or functional perturbations.