Inheritable Memory Defects Induced By Complex Febrile Seizures And The Involved Mechanisms

Febrile seizure (FS) is defined as fever induced seizure which is the most common seizure variant in young children, occurring in3-5%of individuals between age6months and5years. Complex febrile seizures (FSs) are associated with fever that lasts longer than15minutes, occur more than once within24hours. There are conflicts in whether FSs lead to cognition disorder in clinical studies, with population studies show no cognitive deficits in children with FSs and mental retardation is reported in about22%of children with FSs in hospital. A plausible hypothesis is the differences in the severity of the inciting FSs themselves. Here we first took advantage of a well-established rat FSs model to confirm that FSs severity predicted the probability of developing memory deficits in adult. Furthermore, as this effect on memory appeared to last long enough for these rats to bear offspring, we tested whether it was transmitted transgenerationally. Meanwhile, considering the participation of epigenetics in long-term memory formation, we were interested in studying the DNA methylation to explain the long-term and inheritable effect of FSs on memory. Importantly, as there were no efficient drugs to treat with the memory defects after FSs experience, our research provided a potential therapeutic target that is the hypomethylation of memory prompting proteins.In general, our research investigated the effect of different severity of FSs on memory formation and explored the phenomenon of transgenerational transmission together with its mechanism.Inheritable memory defects induced by complex febrile seizures and the involved mechanismsHere we demonstrated that serious FSs warrant the consequent memory defects in Morris water maze, inhibitory avoidance task and contextual fear condition. Furthermore, the memory deficits induced by serious FSs were transgenerationally transmitted to next generation, and in these two generations, DNA methyltransferase (DNMT)1were up-regulated, both of which were rescued by the treatment of DNMT inhibitors. In addition, DNA methylation induced by FSs led to transcriptional silence of the synaptic plasticity gene reelin but not the memory suppressor gene protein phosphatase1(PP1). DNMT inhibitors prevented the hypermethylation of reelin gene. Our study demonstrate that early experience of FSs have an important role in the memory development of brain and epigenetic mechanisms are involved in it. Thus our study suggests more powerful impact of early environmental experiences on neurological diseases.