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

Hai‐Bin Dai,Yang‐Shun Tang,Zhong Chen,Bin Chen,Yun‐Jian Dai,Hua‐Wei Zhao,Yi Wang,Deng‐Chang Wu,Miao‐Miao Jin,Bo Feng

doi:10.1111/cns.13088

Abstract

SummaryAimsFebrile 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.MethodsThe 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.ResultsProlonged 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.ConclusionsOur 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.

Highlights

Behavioral and emotional disorders acquired from early‐life adverse environmental experiences can be transmitted to future offspring.[1,2] These transgenerational transmissions are intriguing and import‐ ant
Little is known whether the memory deficits affected by early‐life neurological disorders could transmit across generations or not
To further confirm the role of DNA methyltransferase (DNMT) in memory defect, we focus on the genes that were related with memory and could be modified by DNA methylation

Summary

Introduction

Behavioral and emotional disorders acquired from early‐life adverse environmental experiences can be transmitted to future offspring.[1,2] These transgenerational transmissions are intriguing and import‐ ant. One of the most important abilities, can be impaired by neurological disorders induced by environmental stimulation in early life.[3] In addition, juvenile‐enriched environment can improve memory formation in both the normal and diseased state, which has been observed in the affected generation as well as in their unaf‐ fected offspring.[4] little is known whether the memory deficits affected by early‐life neurological disorders could transmit across generations or not. Febrile seizures (FSs) induced by early‐life hyperthermia are the most common diseases in childhood.[5,6] As previously re‐ ported that (a) recognition memory impairment is detected after

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