Why do hippocampal mossy cells matter? It depends on the frequency and context

The discrimination of similar episodes and places, and their representation as distinct memories, depend on a process called pattern separation that relies on the circuitry of the hippocampal dentate gyrus (DG). Mossy cells (MCs) are key neurons in the circuitry, but how they influence DG network dynamics, function, and seizure risk has not been fully elucidated. We found the net impact of MCs was inhibitory at physiological frequencies connected with learning and behaviour, and their absence associated with deficits in pattern separation and spatial memory; at higher frequencies, their net impact was excitatory, and their absence protected against seizures. Thus, MCs influence DG outputs in a highly dynamic manner that varies with frequency and context. One-Sentence Summary Hippocampal mossy cells are required for learning and memory; but their absence protects against seizures. ### Competing Interest Statement Denize Atan is on the clinical advisory board of Siloton Ltd.