Stress and Seizures: Space, Time and Hippocampal Circuits

Abstract

Stress is a major trigger of seizures in people with epilepsy. Exposure to stress results in the release of several stress mediators throughout the brain, including the hippocampus, a region sensitive to stress and prone to seizures. Stress mediators interact with their respective receptors to produce distinct effects on the excitability of hippocampal neurons and networks. Crucially, these stress mediators and their actions exhibit unique spatiotemporal profiles, generating a complex combinatorial output with time- and space-dependent effects on hippocampal network excitability and seizure generation.

Keywords: corticosterone; corticotropin-releasing hormone; cortisol; epilepsy; hippocampus; network; neurosteroid; seizure; stress.

Figure 1. The temporal profile of the excitatory and inhibitory actions of stress mediators: plasticity in the epileptic brain

CORT and CRH rapidly increase excitatory transmission within the hippocampus following stress. These actions are mediated by increasing excitatory transmission, and to a lesser extent reducing inhibitory inputs. Over time (hours) the effects of CORT and CRH become inhibitory, through modulation of gene expression and structural plasticity. Neurosteroids act to rapidly curtail some of the pro-excitatory effects of stress (i.e. CORT, CRH) by enhancing GABA_AR-mediated inhibition shortly after stress onset. Under normal conditions such inhibitory mechanisms prevent excessive hippocampal excitability and reduce the risk of seizures (A). However, in the epileptic brain (B), the loss of inhibitory interneurons, alterations in GABA_AR subtype expression and impaired Cl^- homeostasis, results in reduced stress-induced inhibition of the hippocampus and increases the risk of seizures.

Figure 2. Stress mediators exert synapse-specific effects upon excitatory and inhibitory transmission at the DG-CA3 node

A. Simplified schematic representation of the DG-CA3 node comprised of principal cells (grey) and inhibitory interneurons (red). Inset illustrating the effects of endogenous CRH upon CA3 pyramidal spiking and the generation of sharp waves demonstrates how subtle alteration sin neurotransmission at the single cell level can influence network processes (adapted from [55]). B. The effects of stress mediators upon excitatory and inhibitory transmission at specific synapses within the DG-CA3 node. Note that unknown or postulated effects are additionally highlighted.