Abstract
My thesis consists of two projects. The Kcna1-null mouse model of epilepsy was used in both projects. Project I: Spontaneous Recurrent Seizures (SRS), a hallmark of epilepsy, disturb brain homeostasis due to abnormal metabolism, increased neuronal excitability, and ectopic neurogenesis. Tanycytes are specialized ependymal cells lining the third ventricle (3V) and projecting to hypothalamic nuclei. They play a key role in maintaining the brain’s homeostasis. It remains unclear whether tanycytes are affected by SRS or whether metabolic interventions such as the Ketogenic Diet (KD), known to reduce seizure frequency, have a restoring effect on tanycytes. We hypothesized that SRS impacts the tanycytic protein expression in the Kcna1-null mouse model (the SRS group) and the KD has a restoring effect. We investigated changes in the expression of tanycytic proteins GLUT1, GFAP, and DCX and evaluated the impact of a 2-week KD treatment. Compared to controls, SRS mice showed elevated GFAP levels, decreased GLUT1 levels, and no change in DCX levels. The KD treatment did not significantly alter these outcomes, suggesting that while SRS does disrupt tanycytic protein expression, a longer duration of the KD may lead to a restorative effect. Project II: Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Transient apnea associated with Hypoxic-Hypercapnic (HH) conditions are recorded in patients who succumbed to SUDEP, suggesting a potential flaw in chemosensing mechanisms. Previous data showed greater chemoventilatory response in SRS mice after exposure to respiratory challenges compared to WT controls. We focused on chemosensing Orexin neurons and the Locus Coeruleus (LC) neurons and hypothesized that the activation of orexin neurons and LC neurons increases in response to repeated HH and SRS mice have a greater activation. Immunohistochemical co-labeling of orexin – c-Fos (a biomarker of neuronal activation) revealed no change in activation of orexin and LC neurons in WT-SRS pairs of the Triple HH cohort compared to controls at a 30-minute timepoint post the first HH challenge, suggesting that this timepoint was not long enough to observe c-Fos protein peak expression and administering triple HH challenge for a longer duration is required.