Epilepsy results from an imbalance in neuronal excitation and inhibition within the brain. One of the most common forms of epilepsy is temporal lobe epilepsy (TLE), and a large percentage of TLE patients are refractory to medical treatment. TLE is associated with cell loss, gliosis, altered neurogenesis, axon sprouting, and synaptic reorganization in both humans and animal models of TLE. These changes are best described in the hippocampus, which becomes hyperexcitable in epilepsy and can serve as an initiating seizure focus in TLE. In rodent models, there is increased proliferation of adult-born neurons in the hippocampus in TLE, and these new neurons integrate abnormally into neuronal circuits and are believed to contribute to epileptogenesis. Glutamatergic signaling and synapse formation are critical for the proper maturation, synaptic integration, and survival of adult-born dentate granule cells (DGCs), and a recent study demonstrated that hilar mossy cells serve as the first glutamatergic inputs to adult-born DGCs. Interestingly, these hippocampal mossy cells are also highly susceptible to apoptosis after seizures. This suggests that the loss of mossy cells after status epilepticus could alter the maturation and synapse formation by adult-born DGCs and thus the loss of these cells may be a critical step in pathogenesis of epilepsy via its effect on post-seizure neurogenesis. This proposal will investigate how mossy cells contribute to the normal maturation and network integration of adult- born granule cells, and whether mossy cell loss contributes to the abnormal synaptic integration, maturation, and survival of adult-born DGCs in epilepsy. In addition, we will directly test whether the rescue of mossy cell loss prevents alterations in neurogenesis and the development of epilepsy. We will use a mossy cell specific Cre driver mouse line to selectively modify mossy cell activity and survival using pharmacogenetics, diphtheria toxin-mediated cell ablation, and inhibition of apoptosis, and assess changes in adult-born DGC synaptic integration and survival. Additionally, we will combine these techniques with the well-established pilocarpine model of TLE, to assess how mossy cell death affects adult-born DGC maturation and epileptogenesis. We hypothesize that mossy cell activity is critical for proper integration, maturation, and survival of adult-born granule cells and that a reduction in mossy cell loss will restore these features and reduce epileptogenesis after status epilepticus in mice. This study will not only greatly improve our understanding of the role of mossy cells in neurogenesis and epilepsy, but could lead to the development of new therapeutic strategies for many types of refractory epilepsies.
Glutamatergic signaling and synapse formation are critical for the proper integration, maturation, and survival of adult-born dentate granule cells in the hippocampus, and aberrant hippocampal adult neurogenesis likely contributes to the pathogenesis of epilepsy. This proposal will examine how hippocampal mossy cells, the neurons that form the first glutamatergic synapses onto adult-born dentate granule cells, control the integration and survival of these new granule cells, and how the loss of mossy cells contributes to the aberrant development of adult-born granule cells in epilepsy. This study will improve our understanding of neurogenesis and the development of epilepsy, and aid in the generation of new therapeutic approaches to prevent the improper integration of new neurons into the brain.
