The Diverse Roles of Mossy Cells in the Normal Brain, Epileptogenesis, and Chronic Epilepsy

Mossy cells (MCs) of the dentate gyrus (DG) are glutamatergic neurons with the potential for different roles in the normal brain. In epilepsy, particularly temporal lobe epilepsy (TLE), MCs are also considered to be important based on their vulnerability to the brain insults that can cause TLE. Two hypotheses have developed to explain the effects of MC loss in TLE: the dormant basket cell hypothesis suggest that MC death weakens GC inhibition, promoting seizures. The second hypothesis, the irritable mossy cell hypothesis, suggests that those MCs that survive in TLE increase GC excitation. This chapter discusses a “bridging hypothesis” based on the idea that MC functions change depending on the state of the DG network: the normal state, the state during the initial insult of TLE, or during chronic epilepsy in TLE. It is suggested that during the normal state MCs mainly inhibit GCs by activating DG GABAergic neurons. In contrast, during the initial insult, MCs excitation of GCs increases dramatically. After the insult, many of the MCs and hilar GABAergic neurons die due to excitotoxicity. However, some survive, and in chronic epilepsy there are significant structural and functional changes to the circuitry. MCs appear to revert to their mainly inhibitory role. This view reconciles data showing that inhibition of MCs during the initial insult will decrease excitotoxicity, reducing epileptogenesis, but activation of MCs in chronic epilepsy will reduce convulsive seizures. In summary, it is suggested that MCs have diverse roles in the DG that greatly influence the GCs and are different depending on the state of the network.