Mossy Cells in Temporal Lobe Epilepsy

ABSTRACT Temporal lobe epilepsy (TLE) is a disorder with recurrent, debilitating seizures as well as comorbidities that greatly decrease quality of life. Many patients respond poorly to medications, making research important to develop new treatments. A focus of research has been a part of the hippocampus called the dentate gyrus (DG), and a glutamatergic cell type in the DG called the mossy cell (MC). MCs have a direct excitatory projection to the main neuronal cell type, granule cells (GCs), so MCs are theoretically in an important position to regulate the role of the DG in TLE. Although MCs can excite GCs, many investigators consider MC-GC excitation is weak. Instead, MCs are thought to primarily activate DG GABAergic neurons that inhibit GCs. In this proposal we hypothesize that both the excitatory and inhibitory actions of MCs on GCs have important roles, particularly when an initial insult leads to TLE. Our central hypothesis is that during the initial insult, MC excitation of GCs plays a critical role because it strengthens greatly, leading to strong excitation of GC targets and excitotoxicity. In contrast, in chronic epilepsy, we hypothesize a very different MC role. We suggest that MCs resume their normal role to activate DG GABAergic neurons and inhibit GCs, which reduces chronic seizures. Therefore, during the initial insult, MCs should be inhibited for the best outcomes and during chronic epilepsy the MCs should be activated. If supported, this hypothesis would be a paradigm shift by changing the view of MCs in TLE. In addition, the proposed experiments will fill major gaps in knowledge because little is known about MCs during the initial insult, latent period, and chronic epilepsy. Notably, MCs regulate behavior and cognitive tasks in normal mice. We recently showed MCs regulate tasks related to anxiety and cognition, which are comorbidities in TLE. Therefore, we hypothesize a role of MCs in the behavioral comorbidities in TLE. Together these experiments will challenge prevailing views and fill several knowledge gaps about MCs, the DG, and TLE. Furthermore, the experiments will potentially give rise to new approaches for therapeutics.