IL1β Promotes Adult Seizure Susceptibility After Infantile Febrile Seizures Through Upregulating Endocannabinoid System

Epilepsy is a common chronic neurological disorder. About 30% of patient are resistant to two or more antiepileptic drugs and will develop to intractable epilepsy. Although surgery may be considered as an option in some patients with intractable epilepsy, many are not appropriate candidates for surgery. Recurrent epileptic seizures may lead to accidents and cognitive impairment. However, the pathogenesis of epilepsy is still unclear. Therefore, it is urgent to investigate the pathogenesis and find effective treatment of epilepsy. There is a high incidence in children and adolescent, accounting for more than half of the new cases of epilepsy. The outcomes of epilepsy in children and adolescent will be more serious because they are still in the developing stage. The early stage of development is considered as the key stage. Critical events occurred during this stage would play a very important role in epilepsy.Febrile seizures (FS) are the most common type of seizure in infancy and early childhood. Long-term prospective epidemiological studies show that only 3-5% of children with FS develop into temporal lobe epilepsy (TLE) later in adulthood, while retrospective studies demonstrate that adult patients with TLE have a high prevalence (30-50%) of FS in early life. In addition, experimental studies using an animal model of FS in which the predisposing factors (e.g. genetic factors, brain malformation) are excluded, have found that FS rats showed enhanced susceptibility to kainic acid (KA)-induced seizures, suggesting a possible link between childhood FS and adult epilepsy.In addition, traditional anticonvulsant drugs are used to treat FS in children, such as phenobarbital, valproic acid, and phenytoin. These drugs, on one hand, are ineffective in reducing the risk of epileptogenesis; on the other hand, are harmful for immature brian. Therefore, it is urgent and important to develop new strategy to prevent FS and the subsequent epileptogenesis.Inflammatory cytokines have attracted more attention because of their function on modulating epilepsy-induced abnormal neural circuits. Pronounced inflammation, which occurs in acute and lasts hours to days after epilepsy, have been involved in regulating neuron activity and synaptic plasticity. But few studies have explored the role of inflammation-related changes in early brain insults. Recently, it has been demonstrated that children with mutation in IL1β-511 C/T have high risks to FS. Experimental study also found that the proinflammatory cytokine IL-1β is activated after infantile FS. However, it is still not clear whether the cytokine activation in early life is responsible for adult epileptogenensis.Using a well-established experimental FS model, we sought to investigate the relationship between FS and adult epileptogenesis and the role of IL-1β in the epileptogenic process after FS.Pups on postnatal day 8-1-0 were used to develop FS. In briefly, the body temperature of the pups was raised in a warm chamber at 44±0.5℃ for up to 30 min until a seizure was induced with’ confirmed epileptic EEG We found that only the rats that experienced prolonged FS displayed enhanced seizure susceptibility later in adulthood, and this enhancement was blocked by interleukin-1 receptor antagonist (IL1Ra) within a critical time window. IL-1 mimicked the effect of prolonged FS on seizure susceptibility in wild-type mice, while IL1R-/-mice were not susceptible to adult seizures after prolonged FS or IL-1 treatment. The pups that experienced prolonged FS displayed a long-term increase in the expression of cannabinoid type 1 receptor (CB1R) in GABAergic neurons and in CB1R-mediated depolarization-induced suppression of inhibition (DSI), both of which were mimicked by IL-1β administration in early life and reversed by IL1Ra. CB1R blockade or knockdown, or inhibition of endocannabinoid synthesis abolished the enhancement of seizure susceptibility after FS or IL-1β treatment. In addition, CB1R was expressed at a higher level in temporal lobe epilepsy patients with a history of FS.Therefore, our study identifies a previously unrecognized pro-convulsant role of early life IL-1β in epileptogenesis after prolonged FS and further confirms the existence of a crucial and controllable time-window for IL1Ra treatment. These findings indicate that IL-1β may be a new valid target to reduce epilepsy later in adulthood after infantile prolonged FS.