The Role of Dentate Granule Cell Age and Morphology in Seizure-induced Plasticity.

Abstract

Temporal lobe epilepsy (TLE) is a common type of medically intractable epilepsy among adults. In TLE, pathological changes within the hippocampus are hypothesized to play a critical role in epileptogenesis. However, the relationship between observed neuropathology and the development of seizure activity is not well understood. The dentate gyrus is a region of particular interest for epilepsy-related plasticity because of its position as a gate for much of the incoming excitatory input to the hippocampus. In addition, it is capable of a unique type of neuronal plasticity, due to ongoing neurogenesis. DGCs born after an epileptogenic insult in rodent models are much more likely to display aberrant, pro-excitatory morphology than those that were mature at the time of insult. We hypothesized that these adult-born DGCs with aberrant morphology are also the most likely to display pro-excitatory physiological features. Hilar ectopic DGCs are common in tissue from TLE patients and animal models, but rare in healthy controls. We recorded from hilar ectopic and normotopic DGCs from both rat and human TLE tissue and found increased synaptic and intrinsic excitability in rat DGCs, but decreased intrinsic excitability in human DGCs. These data present a conflicting view of the role of ectopic DGCs in hyperexcitability, but they also highlight important discrepancies between the human disease and the rodent disease model. We also hypothesized that adult-born DGCs would contribute more than neonatal-born DGCs to hyper-connectivity of DGCs. We birthdated populations of DGCs using a retrovirus carrying a fluorescent-tagged synaptophysin to study mossy fiber axonal reorganization in the rat pilocarpine TLE model. Interestingly, we found no major differences, either qualitative or quantitative, in axonal plasticity between the two populations. Thus, axonal reorganization does not require adult-neurogenesis in the rat TLE model. The work presented in this dissertation provides new insight into the role of DGC birthdate and morphology for excitability in epilepsy. It is more complex than was previously suggested. We have shown that both neonatal- and adult-born, can exhibit features consistent with increased excitability in TLE, but not all adult-born DGCs appear aberrant.