Mesial temporal lobe epilepsy (MTLE), the most common partial epilepsy, accounts for the majority of patients with uncontrolled seizures. Seizures in MTLE do not strike randomly but occur in daily patterns. Possible influences on the timing of seizures include those factors that underlie circadian oscillation and that facilitate or inhibit seizures. Influences provided by the hypothalamicpituitaryadrenal axis (HPAA) are logical candidates to modulate seizures and will be the focus of the proposed experiments. This proposal examines the temporal distribution of spontaneous, limbic seizures in a unique animal model of partial epileps~ that shares clinical, electrographic, histological, and timing similarities with MTLE.
The specific aim of this proposal is to evaluate the role of endogenous rhythmicity of the HPAA in the circadian modulation of experimental limbic epilepsy. Hypothesis 1. Rhythmicity of the HPAA is intact in experimental epilepsy. Hypothesis 2. Corticosterone releasing hormone (CRH) is differentially affected within the hypothalamus and limbic system by lesions at different levels of the clockHPAA system. Our data suggests that circadian mechanisms continue to function in the epileptic rat and that neuronal density in regions important in HPAA regulation is normal. We will evaluate whether CRH expression remains rhythmic in intact animals as well as in animals that have lesions of the clock or of the HPAA. Hypothesis 3. The normal variations of CRH and corticosterone are necessary for circadian recurrence of limbic seizures. We predict that alterations of inputs into the HPAA will cause changes in the circadian distribution of seizures. Previous results show that seizures occur in an endogenously mediated circadian rhythm.. In summary, these studies will provide insight into the chronoblological factors that facilitate partial seizure expression and may provide new perspectives into treatments for poorly controlled partial epilepsy.
