title: Paternal Aging Affects Behavior in Pax6 Mutant Mice: A Gene/Environment Interaction in Understanding Neurodevelopmental Disorders.
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.
authors.affiliation: Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kaichi
authors.initials: K
authors.lastname: Yoshizaki
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, The Japan Mouse Clinic, RIKEN BRC, Tsukuba, Ibaraki, Japan.
authors.forename: Tamio
authors.initials: T
authors.lastname: Furuse
authors.affiliation: Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kimura
authors.affiliation: Department of Neuroscience and Brain Technologies. Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Valter
authors.initials: V
authors.lastname: Tucci
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, The Japan Mouse Clinic, RIKEN BRC, Tsukuba, Ibaraki, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kaneda
authors.affiliation: Technology and Development Team for Mouse Phenotype Analysis, The Japan Mouse Clinic, RIKEN BRC, Tsukuba, Ibaraki, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.affiliation: Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Osumi
mesh_terms: D000339:Affect; D000375:Aging / Q000473:pathology*; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001522:Behavior, Animal; D005239:Fear; D005260:Female; D059647:Gene-Environment Interaction; D008124:Locomotion; D008297:Male; D008568:Memory; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D065886:Neurodevelopmental Disorders / Q000235:genetics* / Q000473:pathology*; D000071841:PAX6 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D010331:Paternal Age; D010641:Phenotype; D055139:Sensory Gating; D012919:Social Behavior; D014465:Ultrasonics; D014828:Vocalization, Animal
chemical_list: D000071841:PAX6 Transcription Factor; C000605732:Pax6 protein, mouse