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.

Objective

Prolonged fever-induced seizures (febrile status epilepticus [FSE]) during early childhood increase the risk for later epilepsy, but the underlying mechanisms are incompletely understood. Experimental FSE (eFSE) in rats successfully models human FSE, recapitulating the resulting epileptogenesis in a subset of affected individuals. However, the powerful viral and genetic tools that may enhance mechanistic insights into epileptogenesis and associated comorbidities, are better-developed for mice. Therefore, we aimed to determine if eFSE could be generated in mice and if it provoked enduring changes in hippocampal-network excitability and the development of spontaneous seizures.

Methods

We employed C57BL/6J male mice, the strain used most commonly in transgenic manipulations, and examined if early life eFSE could be sustained and if it led to hyperexcitability of hippocampal networks and to epilepsy. Outcome measures included vulnerability to the subsequent administration of the limbic convulsant kainic acid (KA) and the development of spontaneous seizures. In the first mouse cohort, adult naive and eFSE-experiencing mice were exposed to KA. A second cohort of control and eFSE-experiencing young adult mice was implanted with bilateral hippocampal electrodes and recorded using continuous video-electroencephalography (EEG) for 2 to 3 months to examine for spontaneous seizures (epileptogenesis).

Results

Induction of eFSE was feasible and eFSE increased the susceptibility of adult C57BL/6J mice to KA, thereby reducing latency to seizure onset and increasing seizure severity. Of 24 chronically recorded eFSE mice, 4 (16.5%) developed hippocampal epilepsy with a latent period of ~3 months, significantly different from the expectation by chance (P = .04). The limbic epilepsy that followed eFSE was progressive.

Significance

eFSE promotes pro-epileptogenic network changes in a majority of C57BL/6J male mice and frank "temporal lobe-like" epilepsy in one sixth of the cohort. Mouse eFSE may thus provide a useful tool for investigating molecular, cellular, and circuit changes during the development of temporal lobe epilepsy and its comorbidities.

Despite the great diversity of vertebrate limb proportion and our deep understanding of the genetic mechanisms that drive skeletal elongation, little is known about how individual bones reach different lengths in any species. Here, we directly compare the transcriptomes of homologous growth cartilages of the mouse (Mus musculus) and bipedal jerboa (Jaculus jaculus), the latter of which has "mouse-like" arms but extremely long metatarsals of the feet. Intersecting gene-expression differences in metatarsals and forearms of the two species revealed that about 10% of orthologous genes are associated with the disproportionately rapid elongation of neonatal jerboa feet. These include genes and enriched pathways not previously associated with endochondral elongation as well as those that might diversify skeletal proportion in addition to their known requirements for bone growth throughout the skeleton. We also identified transcription regulators that might act as "nodes" for sweeping differences in genome expression between species. Among these, Shox2, which is necessary for proximal limb elongation, has gained expression in jerboa metatarsals where it has not been detected in other vertebrates. We show that Shox2 is sufficient to increase mouse distal limb length, and a nearby putative cis-regulatory region is preferentially accessible in jerboa metatarsals. In addition to mechanisms that might directly promote growth, we found evidence that jerboa foot elongation may occur in part by de-repressing latent growth potential. The genes and pathways that we identified here provide a framework to understand the modular genetic control of skeletal growth and the remarkable malleability of vertebrate limb proportion.