Mossy Cells in Temporal Lobe Epilepsy

PROJECT ABSTRACT Temporal lobe epilepsy (TLE) is a disorder with recurrent, debilitating seizures as well as comorbidities. A focus of research has been the dentate gyrus (DG), which is composed primarily of glutamatergic granule cells (GCs) that provide the output of the DG to hippocampal area CA3. One reason for the attention to the DG is that the GCs can inhibit seizures and also initiate them. GCs also contribute to the hallmark TLE neuropathology called mesial temporal sclerosis (MTS) which contributes to epileptogenesis. Mossy cells (MCs) are another glutamatergic DG cell and innervate GCs, so they are in a position to regulate GCs and seizures. MCs also innervate DG GABAergic neurons, and this action is considered to be strong normally, and leads to inhibition of GCs. We propose a different view, that both the excitatory and inhibitory actions of MCs on GCs have important roles and these roles are especially important in TLE. Our central hypothesis is that MC excitation of GCs strengthens during the initial insult that leads to TLE and this effect promotes epileptogenesis. In contrast, in chronic epilepsy, we hypothesize a very different MC role. We suggest that MCs resume their normal role to primarily activate GABAergic neurons which reduce chronic seizures. Therefore, during the initial insult, MCs should be inhibited for the best outcomes and during chronic epilepsy MCs should be activated. If supported, this hypothesis would be a paradigm shift. In addition, the proposed experiments will fill major gaps in knowledge about MCs and epilepsy. To address the hypothesis, we will use optogenetics and chemogenetics in mouse models of TLE with selective expression of Cre recombinase in MCs. Seizures will be examined as well as comorbidities. Together these experiments will test novel hypotheses and fill several knowledge gaps about epilepsy. Furthermore, the experiments will potentially give rise to new approaches for therapeutics.