Generation of Febrile Seizures and Subsequent Epileptogenesis

Abstract

Febrile seizures (FSs) occur commonly in children aged from 6 months to 5 years. Complex (repetitive or prolonged) FSs, but not simple FSs, can lead to permanent brain modification. Human infants and immature rodents that have experienced complex FSs have a high risk of subsequent temporal lobe epilepsy. However, the causes of FSs and the mechanisms underlying the subsequent epileptogenesis remain unknown. Here, we mainly focus on two major questions concerning FSs: how fever triggers seizures, and how epileptogenesis occurs after FSs. The risk factors responsible for the occurrence of FSs and the epileptogenesis after prolonged FSs are thoroughly summarized and discussed. An understanding of these factors can provide potential therapeutic targets for the prevention of FSs and also yield biomarkers for identifying patients at risk of epileptogenesis following FSs.

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

“…Familial and twin studies have shown that genetic factors contribute significantly to the etiology of FSs (Rich et al 1987, Tsuboi 1987, Tsuboi and Endo 1991), and recent studies have uncovered at least 12 loci associated with FSs (Reviewed in Feng and Chen 2016). Mutations in SCN1A , the gene encoding the α-subunit of the Na v 1.1 voltage-gated sodium channel, are responsible for several epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS).…”

“…Dube et al (2006) subsequently showed that P10 rat pups subjected to prolonged hyperthermia develop spontaneous seizures of hippocampal origin around 3 months of age. In addition, early-life FSs have been associated with a range of biological changes including increased IL- 1β production (Matsuo et al 2006, Feng and Chen 2016), altered expression of hyperpolarization activated cyclic nucleotide-gated (HCN) channels (Chen et al 2001, Brewster et al 2002, Brewster et al 2005), reduced number of astrocyte gap junctions in the hippocampus (Brewster et al 2005), motor map reorganization (Reid et al 2012), enhanced GABA A and benzodiazepine receptor binding (Gonzalez Ramirez et al 2007), reduced expression of GABA B receptor subunits (Han et al 2006), and altered expression of genes involved in stress, inflammation, glial activation, and myelination (Jongbloets et al 2015). Taken together, these studies demonstrate the early-life FSs have long-term pro-epileptic effects in developing rodents.…”

TheDrosophilaERG channelseizureplays a role in the neuronal homeostatic stress response

“…Previous theoretical and empirical studies of neural circuit adaptability, and by extension, the ability of animals to maintain robust and adaptive behavioral outputs in unstable environments, depends on both the intrinsic homeostatic capacity of neurons to maintain an optimal activity pattern, and the ability of neural circuits to maintain stable outputs via the homeostatic regulation of neuronal connectivity and synaptic activity [4-6]. Yet, despite its high incidence, the majority of genetic and molecular factors that regulate neuronal homeostasis, and increase susceptibility to seizures, remain mostly unknown [14-16]. Here, we show that the Drosophila voltage-gated potassium channel sei , a conserved ortholog of the human hERG gene, is required for the neuronal homeostatic response to acute heat stress.…”

“…Previous theoretical and empirical studies have suggested that the neuronal intrinsic robustness depends on the expression and activity of specific combinations of ion channels and transporters, which can vary across neuronal cell types and individuals [7-10]. While some of the transcriptional and physiological processes that enable neurons to adjust their intrinsic activity levels in response to long-term stressors have been identified [11-13], most of the genetic and molecular mechanisms that mediate susceptibility to acute, environmentally-induced seizures, such as fever-induced febrile seizures, remain unknown [14-16].…”

Prolonged febrile seizures induce inheritable memory deficits in rats through DNA methylation

“…Febrile seizures (FSs) induced by early‐life hyperthermia are the most common diseases in childhood . As previously reported that (a) recognition memory impairment is detected after FSs in clinic; (b) deficits in hippocampal working memory and long‐term memory of inhibitory avoidance task have also been demonstrated in animal studies.…”