UC Irvine

Febrile seizures (FSs) are the most common type of seizures in humans. Yet, many of the questions associated with FS remain unresolved. Why do FSs arise? Why do they involve specific developmental ages? Is a genetic predisposition required? A specific type of systemic infection? Does temperature or the rate of change in temperature trigger the seizures? Which fever or other immune mediators are involved? What governs seizure duration? When do the seizures become deleterious? How do we treat them? Similar and additional questions relate to febrile status epilepticus (FSE): Why do some children develop FSE? What are the direct consequences in an otherwise normal brain? In individuals with genetic predisposition (including specific mutations)? What is the mechanism of epileptogenesis? Of cognitive problems? How do we treat them? Can we prevent them? Many of these questions are difficult to resolve in studies involving children. Clear answers require experimental models in which both genetics and environmental factors can be controlled. In addition, the short life span of rodents allows rapid prospective analyses, and the ability to directly study the brain tissue enables mechanistic studies and interventions. Therefore, several models for FS and FSE have been created and employed. These address several issues: the role of specific human mutations in generating FS and FSE, underlying biologic mechanisms that contribute to generation of FS and FSE, the consequences of FSE including epileptogenesis and cognitive deficits, and the pathophysiology of FSE-related epileptogenesis and related comorbidities. Models are also used to test the efficacy of pharmacologic interventions incorporating specific and global immune modulators as well as antagonism of transcriptional and epigenetic pathways. They have also been used to study alternative therapies including microRNA and metabolic approaches. Models have been created in multiple species, from Drosophila and fish to mice and rats. This chapter concludes with the discoveries of the most salient genetic and imposed models which, in the aggregate, enable important contributions to current and future understanding of FS and FSE.