title: A humanoid mouse model of autism.
abstract: Even now fruit of the human genome project is available, we have difficulties to approach neuropsychiatric disorders at the molecular level. Autism is a complex psychiatric illness but has received considerable attention as a developmental brain disorder not only from basic researchers but also from society. Substantial evidence suggests that chromosomal abnormalities contribute to autism risk. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We succeeded to generate mice with a 6.3-Mb-wide interstitial duplication in mouse chromosome 7c that is highly syntenic to human 15q11-13 by using a Cre-loxP-based chromosome-engineering technique. The only paternally duplicated mice display autistic behavioral features such as poor social interaction and stereotypical behavior, and exhibit a developmental abnormality in ultrasonic vocalizations as well as anxiety. The detailed analysis focusing on a non-coding small nucleolar RNA, MBII52, within the duplicated region, revealed that the paternally duplicated mice alter the editing ratio of serotonin (5-HT) 2c receptor pre-mRNA and intracellular calcium responses by a 5-HT2c receptor specific agonist are changed in neurons. This result may explain one of molecular mechanisms of abnormal behaviors in the paternal duplicated mice. The first chromosome-engineered mouse model for human chromosome 15q11-13 duplication fulfills not only face validity of human autistic phenotypes but also construct validity based on human chromosome abnormality. This model will be a founder mouse for forward genetics of autistic disease and an invaluable tool for its therapeutic development.
authors.affiliation: Laboratory of Integrative Bioscience, Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan. takumi@hiroshima-u.ac.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000473:pathology; D002884:Chromosomes, Human, Pair 15; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009474:Neurons / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000235:genetics; D012701:Serotonin / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D044348:Receptors, Serotonin, 5-HT2; D012701:Serotonin