The transgenerational inheritance of reduced memory and recognition in prenatal valproic acid-exposed mice model of autism spectrum disorder

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  • Yoshikawa Misato
    Department of Public Health, School of Pharmacy, Shujitsu University, Japan
  • Aso Hiroaki
    Department of Public Health, School of Pharmacy, Shujitsu University, Japan
  • Watanabe Masahiko
    Department of Public Health, School of Pharmacy, Shujitsu University, Japan
  • Suemaru Katsuya
    Department of Public Health, School of Pharmacy, Shujitsu University, Japan

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<p>Background: Autism spectrum disorder (ASD) is a pervasive developmental disorder characterized by two core behavioral symptoms of social deficits and stereotyped/repetitive behaviors. Both genetic and environmental factors are involved in the pathogenesis of ASD. Environmental factors include prenatal exposure to drugs, such as valproic acid (VPA) which is an antiepileptic drug and histone deacetylase (HDAC) inhibitor. HDAC inhibition causes the changes in gene expression of ASD-related molecules. We investigated whether behavioral deficits in prenatally VPA-exposed ASD model mice are transmitted to the next generation (F2).</p><p>Methods: VPA was administered intraperitoneally to the pregnant mice at 300 mg/kg dosage on embryonic day 10 (E10) and 400 mg/kg on E12. Next we mated the VPA-exposed F1 male offspring with F1 female offspring to obtain F2 mice, and then evaluated the function of sociability and memory/recognition in F2 mice.</p><p>Results: The F1 male offspring have showed impaired sociability and preference for social novelty in the three-chambered social test and spatial memory in Morris water maze test. The F1 female offspring have showed impaired spatial memory only. F2 male offspring decreased the function of preference for social novelty and spatial memory in Morris water maze test, and object recognition memory in novel object recognition test, but not sociability. </p><p>Conclusions: Sociability deficit in the offspring from VPA-treated mother mice wasn't transmitted to F2 offspring. But F2 mice showed reduced social, spatial, and object recognition memory, indicating perirhinal cortex and hippocampus related memory impairments. These results suggest that prenatal exposure to VPA affects gene expression in the memory and recognition related brain area as an epigenetic change. </p>

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