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

Abstract

Summary Aims Febrile seizures (FSs) are the most common types of seizures in young children. However, little is known whether the memory deficits induced by early‐life FSs could transmit across generations or not. Methods The memory functions of different generations of FS rats were behaviorally evaluated by morris water maze, inhibitory avoidance task, and contextual fear conditioning task. Meanwhile, molecular biology and pharmacological methods were used to investigate the role of DNA methylation in transgenerational transmission of memory defects. Results Prolonged FSs in infant rats resulted in memory deficits in adult and transgenerationally transmitted to next generation, which was mainly through mothers. For these two generations, DNA methyltransferase (DNMT) 1 was upregulated, leading to transcriptional inhibition of the synaptic plasticity protein reelin but not the memory suppressor protein phosphatase 1. DNMT inhibitors prevented the high expression of DNMT1 and hypermethylation of reelin gene and reversed the transgenerationally memory deficits. In addition, enriched environment in juvenile rats rescued memory deficits induced by prolonged FSs. Conclusions Our study demonstrated early experience of prolonged FSs led to memory deficits in adult rats and their unaffected offspring, which involved epigenetic mechanisms, suggesting early environmental experiences had a significant impact on the transgenerational transmission of neurological diseases.

MicroRNA expression profiling after recurrent febrile seizures in rat and emerging role of miR-148a-3p/SYNJ1 axis

“…The diagram confirmed that the DNMT1 gene is a target of miR148a-3p and that there is a close relationship between DNMT1 and the occurrence and development of epilepsy 38 . In addition, epigenetic regulation plays vital roles in nervous system diseases 39 . Among the predicted target genes were many genes strictly related to neuroimmune function, such as SYNJ1, Noggin (NOG), Neuronplastin (NPTN), Nuclear receptor coactivator 1 (NCOA1), and SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2).…”

Augmented seizure susceptibility and hippocampal epileptogenesis in a translational mouse model of febrile status epilepticus

“…The presence of increased susceptibility to chemoconvulsants suggests that hippocampal networks were enduringly altered by the eFSE in a “pro‐epileptogenic” manner. Whereas the current work has not examined memory deficits in eFSE mice, cognitive problems have been robustly identified in eFSE rats, including those who did not develop frank epilepsy 19,55 . Hence, eFSE mice should provide a useful instrument to study hippocampal changes that compromise cognitive functions, a problem now emerging in eFSE‐experiencing children 9 …”

“…Whereas the current work has not examined memory deficits in eFSE mice, cognitive problems have been robustly identified in eFSE rats, including those who did not develop frank epilepsy. 19,55 Hence, eFSE mice should provide a useful instrument to study hippocampal changes that compromise cognitive functions, a problem now emerging in eFSE-experiencing children. 9 Interictal spike series and recurrent spontaneous seizures developed in 4 of 24 chronically recorded eFSE-experiencing mice, and no interictal spike series or seizures were identified in euthermic control mice or in mice that had hyperthermia of the same degree and duration but in which eFSE was prevented using diazepam.…”

Structure‐based discovery of CZL80, a caspase‐1 inhibitor with therapeutic potential for febrile seizures and later enhanced epileptogenic susceptibility

“…Then they were moved back to the hyperthermia chamber to elicit the 2nd seizure. For inducing prolonged FS (Dai et al, 2019; Wu et al, 2017), the pups were moved to a cool surface for 2 min once seizure was evoked. Then they were moved back to the hyperthermia chamber.…”