Psychiatric comorbidities in epilepsy contribute significantly to the disease burden of epilepsy, a problem which is now increasingly recognized by clinicians, scientists, patient advocacy groups and the federal government. Indeed, 40% of patients with epilepsy suffer from stress-related psychopathologies such as anxiety and depression. Animal models of epilepsy corroborate clinical observations, evident as an array of depressive and anxiety-like phenotypes. Together these observations are suggestive of a common etiological mechanism that may influence disease progression of epilepsy itself and of its comorbidities. Recent clinical and preclinical evidence suggests that abnormalities in the stress system may contribute to epilepsy development and progression, as well as the development of psychiatric comorbidities. To date, however, very few mechanistic studies have been conducted to elucidate the relationship between stress hormone dysregulation and the development of epilepsy or its comorbidities. Patients and animals with epilepsy exhibit chronic hyperactivity of the hypothalamic-pituitaryadrenocortical (HPA) axis, which regulates the stress response, resulting in chronically elevated glucocorticoids and over-activation of glucocorticoid receptors; a feature shared with major depression. Elevated glucocorticoids can damage neurons, increase brain excitability (pro-convulsant) and induce depressive symptoms in rodents and people. Thus we propose that HPA axis dysfunction in epilepsy contributes to disease progression and the development of psychiatric comorbidities. Our guiding hypothesis, therefore, is that the comorbid development of epilepsy and depression is mediated by chronic hyper-activation of the glucocorticoid stress receptor (GR). We will test this hypothesis utilizing the well-characterized pilocarpine mouse model of temporal lobe epilepsy. In these animals, we will temporally and conditionally delete the glucocorticoid receptor in forebrain regions implicated in epilepsy and stress-regulation. We predict that such temporal and region-specific glucocorticoid receptor deletion will have disease modifying effects in epilepsy, evident as reduced seizures and reduced comorbid depressive-like behaviors. These studies will lay the groundwork for developing a mechanistic understanding of the relationship between stress and epilepsy, and will aid in the development of novel therapies.
Stress hormones are dramatically increased during the development of epilepsy, and are chronically dysregulated after the disease develops. The experiments outlined in this application seek to understand the mechanisms by which the stress circuitry is involved in epileptogenesis and the development of depression and anxiety in epilepsy. Our efforts have the potential to lead to entirely new approaches to treat epilepsy and its psychiatric comorbidities.
