THE SITE-SPECIFIC EFFECTS OF KINDLING ON COGNITION AND ADULT HIPPOCAMPAL NEUROGENESIS

Abstract

Nearly 1.5% of the general population is affected by epilepsy. Despite a long history of research and clinical endeavors to combat the disease, in 1 of 3 cases, epilepsy is intractable and resistant to medication treatment. Current pharmacological strategies target seizure onset as the primary manifestation of illness; however, patients with advanced stages of the disease suffer from a wide array of psychiatric comorbidities. Anxiety, depression and memory deterioration are the chief complaints of epileptic patients delegated from neurologic to psychiatric care.

Temporal lobe epilepsy is the most resistant form of epilepsy and the form that is most complicated by the presence of psychiatric and cognitive comorbidities that are increasingly recognized as critical factors in long-term patient care. These comorbidities are independent risk factors for poor quality of life. In fact, studies have shown that in patients with epilepsy, co- morbid factors correlate more strongly with poor quality of life than does seizure frequency. At present, the behavioural comorbidities associated with temporal lobe epilepsy are poorly understood, and their management is difficult because many commonly prescribed anticonvulsant drugs make them worse. Therefore, even patients with some degree of seizure control often continue to experience debilitating behavioural problems that impair their daily living.

This thesis attempts to understand the impact of seizures originating from different brain sites. The research described in this thesis was conducted using an animal model called kindling to investigate the hypothesis that seizure-induced alterations in hippocampal neurogenesis play a significant role in the cognitive deficits associated with epilepsy. The experiment used 25 adult male rats. Rats were divided into four group: hippocampal kindled (n = 6), amygdala kindled (n = 7), caudate nucleus kindled (n = 6) and control rats (n = 6). Kindled rats received 99 electrical stimulations delivered to the appropriate brain region through an implanted bilateral electrode. At the end of the kindling phase, rats were subjected to a fear conditioning paradigm to assess cognitive behavior. After the fear conditioning, rats were sacrificed and immunohistochemical analyses were done to assess the impact of seizures on hippocampal neurogenesis and neuronal activation. The results indicated that there is a significant deterioration of cognitive performance following long-term limbic kindling (i.e., hippocampal and amygdala kindling only). This was accompanied by an increase in hippocampal neurogenesis that was paralleled with low expression of immediate early genes. Collectively, these findings enhance our understanding of mechanisms underlying the behavioral co- morbidities associated with temporal lobe epilepsy and demonstrate the link between adult neurogenesis and cognitive impairments following long-term kindling of limbic brain regions.