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Stress
Stress is considered a risk factor for developing epilepsy as well as having the potential to induce seizures themselves despite the body’s homeostatic mechanisms to protect against stress. Stress is one of the most frequently self-reported triggers in people with epilepsy. Additionally, the severity, duration, and time point that the stress occurs during development contribute to risk of developing epilepsy later. The effects of stress are caused by hormones released in response. They act on a vast array of receptors throughout the body, but the region most sensitive to stress is the hippocampus with a high density of stress hormone receptors. Stress hormones cause hyper-excitability of cells in the brain or neurons when the bind to their receptors, which is what makes people more susceptible to seizures.

Corticosteroid Effects on the Hippocampus
Corticosteroids- cortisol in humans and corticosterone in mice- are one class of hormones released from the adrenal glands in response to stress. They bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the hippocampus, but also bind to receptors in all organs and tissues in the body. Stress can affect the body on multiple time-scales: fast rapid effects that take place within seconds and minutes, and long-term effects that take place over days and months. Rapid effects are caused by the activation of cell surface MRs which result in increased frequency of excitatory postsynaptic potentials and decreased frequency of inhibitory postsynaptic potentials. Together these changes cause hyper-excitability of neurons in the hippocampus leading to an increased risk of seizures immediately following the onset of stress. Long-term effects of stress are mediated by nuclear MRs and GRs. When stress hormones bind to these nuclear receptors they alter gene expression in neurons. This results in a variety of downstream effects. One effect is the altered expression of the gene that codes for calcium channels so that it is slowed. The slowed production of calcium channels for the membrane results in prolonged hyperpolarization of the cell after firing an action potential, thus effectively decreasing how often neurons can fire and decreasing the potential for hyper-excitability of the cells. Therefore, the long-term effects of stress can serve to protect against the effects of stress itself. However, with chronic stress exposure the homeostatic mechanisms that protect against stress are disrupted and without them the brain is again at risk of hyper-excitability and seizures.

Corticotropin-Releasing Hormone Effects on the Hippocampus
Corticotropin-releasing hormone (CRH) is another hormone released in response to stress. It is a precursor to corticosteroids that is released from the hypothalamus. It binds to receptors in the anterior pituitary which releases adrenocorticotropic hormone (ACTH), which then acts on the adrenal cortex to release corticosteroids. Its effects are similar to corticosteroids in promoting hyper-excitability in neurons in the hippocampus, but the mechanisms by which it acts are less understood. Studies have shown that immediate short-term effects include shortening the hyperpolarization phase following an action potential which results in the increase of the frequency that neurons can fire and causes hyper-excitability. Long-term effects of CRH in the brain result from chronic exposure stress and high levels of CRH. Studies have shown that CRH decreases the number of dendritic spines on the neurons in the hippocampus.