Epilepsy and synaptic reorganization in models of status epilepticus and hypoxia-ischemia

Abstract

Synaptic reorganization is a process where new circuits are formed and neuronal populations are abnormally interconnected. These altered circuits are commonly associated with hippocampal sclerosis in humans with temporal lobe epilepsy. This thesis examines the relationship between synaptic reorganization and epilepsy in four different models of brain injury. Chapter 2 attempted to eliminate mossy fiber sprouting (i.e., synaptic reorganization in the dentate gyrus) following pilocarpine induced status epilepticus, by pre-treating rats with a protein synthesis inhibitor, in order to examine the effect that lack of mossy fiber sprouting would have on epileptogenesis following status epilepticus. Chapter 3 examined the hippocampal electrophysiology along the septotemporal axis in kainate-treated epileptic rats, and found a strong association between septotemporal differences in synaptic reorganization and abnormal electrophysiology. Chapters 4 and 5 utilized a hypoxic-ischemic model in young adult and perinatal rats to induce a unilateral lesion that involved the hippocampus for the purpose of examining the potential for inducing mossy fiber sprouting after a hypoxic-ischemic injury. Synaptic reorganization in the dentate gyrus is a model for analyzing the effects that the new abnormal circuits have on a neuronal population, and the data in this thesis demonstrates that mossy fiber sprouting is a common occurrence following brain injury. This process can occur in other regions (i.e., CA1) and probably commonly occurs at other sites of injury (i.e., focal neocortical infarct). These new circuits may have a restorative function under normal conditions, but may act as a substrate for abnormal behavior in states that range outside the usual. Thus it is the goal of this research to understand how and where synaptic reorganization occurs in models of brain injury, and the physiological conditions that induces these new circuits to express abnormal function.