Paternal Aging Affects Behavior in Pax6 Mutant Mice: A Gene/Environment Interaction in Understanding Neurodevelopmental Disorders.

Kaichi Yoshizaki,Valter Tucci,Tamio Furuse,Ryuichi Kimura,Hideki Kaneda,Noriko Osumi,Shigeharu Wakana,Kazutaka Ikeda

doi:10.1371/journal.pone.0166665

Kaichi Yoshizaki, Valter Tucci + Show 6 more

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https://doi.org/10.1371/journal.pone.0166665

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Abstract

Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD) have increased over the last few decades. These neurodevelopmental disorders are characterized by a complex etiology, which involves multiple genes and gene-environmental interactions. Various genes that control specific properties of neural development exert pivotal roles in the occurrence and severity of phenotypes associated with neurodevelopmental disorders. Moreover, paternal aging has been reported as one of the factors that contribute to the risk of ASD and ADHD. Here we report, for the first time, that paternal aging has profound effects on the onset of behavioral abnormalities in mice carrying a mutation of Pax6, a gene with neurodevelopmental regulatory functions. We adopted an in vitro fertilization approach to restrict the influence of additional factors. Comprehensive behavioral analyses were performed in Sey/+ mice (i.e., Pax6 mutant heterozygotes) born from in vitro fertilization of sperm taken from young or aged Sey/+ fathers. No body weight changes were found in the four groups, i.e., Sey/+ and wild type (WT) mice born to young or aged father. However, we found important differences in maternal separation-induced ultrasonic vocalizations of Sey/+ mice born from young father and in the level of hyperactivity of Sey/+ mice born from aged fathers in the open-field test, respectively, compared to WT littermates. Phenotypes of anxiety were observed in both genotypes born from aged fathers compared with those born from young fathers. No significant difference was found in social behavior and sensorimotor gating among the four groups. These results indicate that mice with a single genetic risk factor can develop different phenotypes depending on the paternal age. Our study advocates for serious considerations on the role of paternal aging in breeding strategies for animal studies.

Highlights

Autism spectrum disorders (ASD) and attention deficit and hyperactivity disorder (ADHD) are the most frequent neurodevelopmental disorders that receive diagnosis early in childhood
Since ultrasonic vocalization (USV) in pups is considered to be a mother call related to anxiety and perception of temperature [54, 55], Sey/+ pups born from young father may exhibit a lower level of responsiveness to anxiety or less perception of temperature induced by maternal separation compared with the wild type (WT) littermates
WT pups born from aged father exhibited a tendency of decrease in USV calls, which was not statistically different from WT pups born from young father

Summary

Introduction

Autism spectrum disorders (ASD) and attention deficit and hyperactivity disorder (ADHD) are the most frequent neurodevelopmental disorders that receive diagnosis early in childhood. These developmental conditions have progressively increased in recent year, causing a significant burden for the society [1, 2]. ASD exhibits complex symptoms, which include abnormalities in social interaction and repetitive behaviors. ASD patients often exhibit motor deficits, sensorimotor dysfunction, epilepsy and anxiety, and in some cases it has been reported the presence of ADHD symptoms [3,4,5,6,7,8]. Recent genome-wide screening of candidate genes has indicated clustering of molecules involved in synaptic signaling and chromatin remodeling as plausible targets [15, 16]

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