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Characterization of Kindling's effects on spatial cognition : implications for the mechanisms of Kindling-induced mnemonic dysfunction



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Kindling refers to a procedure in which repeated electrical stimulation of a discrete brain region is used to evoke seizures that progress in their severity with successive stimulations. This process results in enduring changes in brain function that are manifest in an enhanced susceptibility to seizure-evoking stimuli and alterations in at least some types of behavior. In my dissertation, I investigated the relation between brain changes associated with epileptogenesis induced by kindling and spatial cognition in rats. This topic is of interest for both its clinical relevance to memory dysfunction observed in patients with epilepsy and the insights it may provide into the mechanisms underlying learning and memory function. My approach was twofold. First, I examined the effects of kindling on a wide variety of behavioral tasks in order to characterize the nature of the effects of kindling on spatial cognition. Second, because kindling produces a collage of brain changes, some of which, at least, vary in relation to the site of the electrode used for kindling, the severity of the seizures elicited, and the interval since the last kindling stimulation, I investigated the relation between these kindling-related variables and behavioral task performance. In a series of studies, I investigated the effects of (i) kindling in the dorsal hippocampus (dHPC), perirhinal cortex (PRH), or amygdala (AM), (ii) kindling until partially or fully generalized seizures were elicited, and (iii) testing at intervals from one to 28 days following kindling on tasks that assessed sensorimotor functions, motivation, anxiety, object-related cognition, and spatial cognition in rats. I found that kindling was capable of producing highly selective and enduring behavioral effects, which varied depending upon the site being kindled and the severity of the seizures elicited. These included: (i) a selective disruption of spatial learning, which was produced by kindling in the dHPC but not in the PRH or AM and by kindling of fully generalized but not partially generalized seizures, (ii) a partially selective impairment of object-related mnemonic functions, which was produced by kindling in the PRH but not the AM or dHPC, and (iii) an anxiogenic effect, which was produced by kindling in the PRH or AM but not the dHPC. Based on these findings, I generated a specific hypothesis regarding the underlying mechanisms of the effects of kindling on spatial mnemonic function as follows. Epileptogenesis disrupts spatial learning through metaplastic effects that alter hippocampal mechanisms regulating induction of experience-dependent plasticity. Consistent with this hypothesis, kindling has been shown to produce enduring changes in factors that might be expected to alter plasticity including NMDA receptor function, PKC activity, and CA++ channel density. Importantly, available evidence suggests that these effects show a relation to the site and extent of kindling that is consistent with the conditions under which the deficit is observed. This hypothesis makes a variety of novel, testable predictions and, if verified, would provide evidence in support of the proposed role of synaptic plasticity in experience-dependent behavioral change. It would also offer a potential target for therapeutic interventions aimed at treating epilepsy-associated mnemonic dysfunction.





Doctor of Philosophy (Ph.D.)







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