Alterations and Imbalance of Dorsal and Ventral Mossy Cells in a Mouse Model of Epilepsy

Abstract

Mossy cells (MCs) in the hilus of the dentate gyrus (DG) are important for regulating activity of dentate granule cells and are particularly vulnerable to excitotoxic damage in epilepsy. Recent studies have demonstrated that MCs in the dorsal and ventral DG differ in the patterns of their axonal projections and neurochemical identities. Such differences raised questions about the vulnerability and plasticity of dorsal and ventral MCs in epilepsy and led to this study using a mouse pilocarpine model of epilepsy. Dorsal MCs were labeled by transfection of Cre-dependent eYFP in the dorsal DG of Calcrl-Cre mice that express Cre selectively in MCs. Ventral MCs were labeled with calretinin (CR), which labels ventral but not dorsal MCs. At 6-8 weeks after pilocarpine treatment, MC loss and axonal projections of remaining MCs were studied in control and pilocarpine-treated mice with confocal microscopy. Dorsal MCs were severely depleted, but many ventral MCs remained, and quantitative analysis of GluA2-labeled hilar neurons demonstrated a proportionally greater loss of dorsal MCs (77.6% loss) than ventral MCs (21.5% loss). Loss of dorsal MCs led to a marked reduction in the dorsal commissural pathway, while the remaining ventral MCs maintained a prominent, though reduced, ventral to dorsal association pathway. In pilocarpine-treated animals, a plexus of CR-labeled fibers extended into the middle molecular layer, suggesting axonal sprouting of remaining ventral MCs, with some of these fibers in contact with parvalbumin-labeled dendrites. These findings suggest that dorsal and ventral MCs differ in their vulnerability to seizure-induced damage in this animal model, creating an imbalance between the dorsal and ventral MC pathways that could alter the excitatory/inhibitory balance within the dentate gyrus.