Date of Award
Doctor of Philosophy (PhD)
Neuronal damage and synaptic reorganization are two common neuropathological changes repeatedly detected in human epilepsy patients and animal models of epilepsy. To date, the relationship between cell loss, axonal growth, and epileptogenesis remains unclear. However, it is proposed that neuronal damage within the hilar area and mossy fiber sprouting alter the balance of excitation and inhibition within the epileptic brain, and contribute to the development of seizures. The axonal sprouting is suggested to be triggered by either cell loss or by excessive neuronal activity, or both. In the present study, we tested epileptogenesis and seizure-related morphological changes in several rat strains, including the Wistar strain and Long-Evans hooded strains, and the kindling-prone (FAST) and kindling-resistant strains (SLOW) created at McMaster University. These strains were tested using both KA- and pilocarpine-induced status epilepticus models. Although the Wistar and the Long-Evans hooded strains respond similarly to KA or pilocarpine-induced SE, we found that the Wistar rat strain showed a reliable neuronal loss and more severe neuronal growth, while the Long-Evans strain showed no detectable neuron damage and moderate axonal sprouting. The mossy fiber system was also significantly different between the FAST and the SLOW strains, and responded differently to seizure activity. This evidence suggests that genetic factors might be important for the induction of seizure-related morphological changes. In addition to the strain differences in seizure development, axonal growth and neuronal loss, it has been shown that epilepsy and synaptic reorganization can be developed independently of gross neuronal loss within the hilar area. Thus, it is clear that neuronal damage within the hilus is neither a crucial prerequisite, nor a necessary consequence of epileptogenesis or axonal growth. Our results favour the postulate that epilepsy-related axonal growth is at least partly triggered by excessive neuronal activity and contributes to the development of seizures. We have also tested the modulation of axonal growth and kindling development by infusing factors that affect axonal patterning and pathway finding during neuronal development, such as Neurotrophin-3 (NT-3), or axonal guidance molecules, the Eph receptors and the ephrins, into adult CNS. Continuous infusion of NT-3, or agents that affect the function of EphA receptors and ephrins, alters kindling epileptogenesis and the extent and pattern of mossy fiber sprouting in adult rats. Thus, we have shown that such factors preserve their functions into adulthood, and regulate activity-dependent axonal growth in the kindling model. Agents that affect the function of these molecules dramatically alter both kindling induction and mossy fiber sprouting. Therefore, it is likely that neurotrophic factors and axonal guidance molecules preserve their function into adulthood, modulating neuronal plasticity, epileptogenesis and synaptic reorganization in adult CNS.
Xu, Bin, "Axonal growth, neuronal damage and epileptogenesis" (2001). Open Access Dissertations and Theses. Paper 2564.