Dataset Information

Transient increase of interleukin-1? after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling.

ABSTRACT: It remains unclear how infantile febrile seizures (FS) enhance adult seizure susceptibility. Here we showed that the transient increase of interleukin-1? (IL-1?) after prolonged FS promoted adult seizure susceptibility, which was blocked by interleukin-1 receptor antagonist (IL-1Ra) within a critical time window. Postnatal administered IL-1? alone mimicked the effect of FS on adult seizure susceptibility. IL-1R1 knockout mice were not susceptible to adult seizure after prolonged FS or IL-1? treatment. Prolonged FS or early-life IL-1? treatment increased the expression of cannabinoid type 1 receptor (CB1R) for over 50 days, which was blocked by IL-1Ra or was absent in IL-1R1 knockout mice. CB1R antagonist, knockdown and endocannabinoid synthesis inhibitor abolished FS or IL-1?-enhanced seizure susceptibility. Thus, this work identifies a pathogenic role of postnatal IL-1?/IL-1R1 pathway and subsequent prolonged prominent increase of endocannabinoid signaling in adult seizure susceptibility following prolonged FS, and highlights IL-1R1 as a potential therapeutic target for preventing the development of epilepsy after infantile FS.

SUBMITTER: Feng B

PROVIDER: S-EPMC4763292 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling.

Feng Bo B Tang Yangshun Y Chen Bin B Xu Cenglin C Wang Yi Y Dai Yunjian Y Wu Dengchang D Zhu Junmin J Wang Shuang S Zhou Yudong Y Shi Liyun L Hu Weiwei W Zhang Xia X Chen Zhong Z

Scientific reports 20160223

It remains unclear how infantile febrile seizures (FS) enhance adult seizure susceptibility. Here we showed that the transient increase of interleukin-1β (IL-1β) after prolonged FS promoted adult seizure susceptibility, which was blocked by interleukin-1 receptor antagonist (IL-1Ra) within a critical time window. Postnatal administered IL-1β alone mimicked the effect of FS on adult seizure susceptibility. IL-1R1 knockout mice were not susceptible to adult seizure after prolonged FS or IL-1β trea ...[more]

PMID: 26902320

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Project description:ObjectiveADGRV1 gene encodes adhesion G protein-coupled receptor-V1 that is involved in synaptic function. ADGRV1 mutations are associated with audio-visual disorders. Although previous experimental studies suggested that ADGRV1 variants were associated with epilepsy, clinical evidence is limited and the phenotype spectrum is to be defined.MethodsTrio-based targeting sequencing was performed in a cohort of 101 cases with febrile seizure (FS) and epilepsy with antecedent FS. Protein modeling was used to assess the damaging effects of variants. The genotype-phenotype correlations of the ADGRV1 variants in epilepsy and audio-visual disorders were analyzed.ResultsADGRV1 variants were identified in nine unrelated cases (8.91%), including two heterozygous frameshift variants, six heterozygous missense variants, and a pair of compound heterozygous variants. These variants presented a statistically higher frequency in this cohort than that in control populations. Most missense variants were located at CalX-β motifs and changed the hydrogen bonds. These variants were inherited from the asymptomatic parents, indicating an incomplete penetrance. We also identified SCN1A variants in 25 unrelated cases (24.75%) and SCN9A variants in 3 unrelated cases (2.97%) in this cohort. Contrary to SCN1A variant-associated epilepsy that revealed seizure was aggravated by sodium channel blockers, ADGRV1 variants were associated with mild epilepsy with favorable responses to antiepileptic drugs. The patients denied problems with audio-visual-vestibular abilities in daily life. However, audio-visual tests revealed auditory and visual impairment in the patient with compound heterozygous variants, auditory or vestibular impairment in the patients with heterozygous frameshift, or hydrogen-bond changed missense variants but no abnormalities in the patients with missense variants without hydrogen-bond changes. Previously reported ADGRV1 variants that were associated with audio-visual disorders were mostly biallelic/destructive variants, which were significantly more frequent in the severe phenotype of audio-visual disorders (Usher syndrome 2) than in other mild phenotypes. In contrast, the variants identified in epilepsy were monoallelic, missense mainly located at CalX-β, or affected isoforms VLGR1b/1c.SignificanceADGRV1 is potentially associated with FS-related epilepsy as a susceptibility gene. The genotype, submolecular implication, isoforms, and damaging severity of the variants explained the phenotypical variations. ADGRV1 variant-associated FS/epilepsy presented favorable responses to antiepileptic drugs, implying a clinical significance.

Dataset Information

Transient increase of interleukin-1? after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling.

Publications

Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling.

Similar Datasets

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