Rapid, coordinate inflammatory responses after experimental febrile status epilepticus: Implications for epileptogenesis

Abstract

Epilepsy is a common neurological disorder with many causes. For temporal lobe epilepsy antecedent insults are typically found. These risk factors include trauma or history of long fever-associated seizures (febrile status epilepticus) in childhood. Whereas the mechanisms by which such insults promote temporal lobe epilepsy are unknown, an extensive body of work has implicated inflammation and inflammatory mediators in both human and animal models of the disorder. However, direct evidence for an epileptogenic role for inflammation is lacking. Here we capitalized on a model where only a subgroup of insult-experiencing rodents develops epilepsy. We reasoned that if inflammation was important for generating epilepsy, then early inflammation should be more prominent in individuals destined to become epileptic compared to those that will not become epileptic. In addition, the molecular and temporal profile of inflammatory mediators would provide insights into which inflammatory pathways might be involved in the disease process. We examined inflammatory profiles in hippocampus and amygdala of individual rats and correlated them with a concurrent non-invasive, amygdalar magnetic resonance imaging epilepsy-predictive marker. We found significant individual variability in the expression of several important inflammatory mediators, but not in others. Of interest, a higher expression of a subset of hippocampal and amygdalar inflammatory markers within the first few hours following an insult correlated with the epilepsy-predictive signal. These findings suggest that some components of the inflammatory gene network might contribute to the process by which insults promote the development of temporal lobe epilepsy.

Significance Statement: Epilepsy is a devastating brain disorder affecting ∼1% of the world population. Epilepsy may arise because of genetic factors or may follow an insult or inciting event. A common antecedent of limbic, temporal-lobe epilepsy is a history of long febrile seizures in childhood. However, for unknown reasons only some individuals with these early-life seizures develop epilepsy. In our immature rat model of long febrile seizures, as in children, only some individuals progress to epilepsy, enabling us to address the mechanisms for these divergent outcomes. Here we find that a robust activation of some inflammatory mediators distinguishes individual rats that develop a predictive marker of epilepsy from those who do not.