Cognitive Impairment and Aberrant Plasticity in the Kindling Model of Epilepsy

Abstract

Epilepsy is a neurological disorder that affects approximately 1% of the population worldwide. Although motor seizures are the best known feature of epilepsy, many patients also experience severe interictal (between-seizure) behavioral and cognitive comorbidities that have a greater negative influence on quality of life than seizure control or frequency. To study the characteristics of these interictal comorbidities and the neural mechanisms that underlie them, I use the kindling model of epilepsy. Kindling refers to the brief electrical stimulation of a discrete brain site that produces a gradual and permanent increase in the severity of elicited seizure activity. The repeated seizures associated with kindling induce robust structural and functional plasticity that appears to be primarily aberrant. Importantly, the aberrant plasticity evoked by repeated seizures is thought to contribute to the pathophysiology of epilepsy and its associated behavioral and cognitive comorbidities. Unfortunately, the relationship between aberrant plasticity and cognition dysfunction following repeated seizures remains poorly understood. The aim of this dissertation is to gain a better understanding of the effects of repeated convulsions on aberrant neural plasticity and interictal behavior. In Chapter 2, I will examine the effect of short- and long-term amygdala kindling on amygdala- and hippocampal-dependent forms of operant fear conditioning. To evaluate whether kindling alters neural circuits important in memory, I will analyze post-mortem measures of neural activity following the retrieval of fearful memories. In Chapter 3, I will evaluate whether deficits in operant fear learning and memory are a general consequence of convulsions induced by kindling stimulations or whether these deficits occur following kindling of specific brain regions. To evaluate whether aberrant plasticity following kindling of different brain regions contributes to learning and memory deficits, I will make post-mortem examinations of the inhibitory neurotransmitter neuropeptide Y and its Y2 receptor. In Chapter 4, I will investigate the relationship between hippocampal neurogenesis and cognition. Specifically, I will determine whether kindling of different brain regions induces an aberrant form of hippocampal neurogenesis that contributes to cognitive dysfunction. In Chapter 5, I will investigate whether kindling of different brain regions alters different subpopulations of hippocampal GABAergic interneurons, in terms of number and morphological features. Finally, Chapter 6 will provide preliminary evidence that the cognitive impairments associated with kindling can be ameliorated through intrahippocampal infusions of recombinant reelin. The collection of studies in this dissertation improves our understanding of the relationship between aberrant plasticity and cognitive impairments associated with repeated convulsions.