Behavioral and neuromorphological characterization of a novel Tuba1 mutant mouse

• Published in: Behavioural brain research 2012-02, Vol.227 (1), p.167-174
• Main Authors: Furuse, Tamio, Yamada, Ikuko, Kushida, Tomoko, Masuya, Hiroshi, Miura, Ikuo, Kaneda, Hideki, Kobayashi, Kimio, Wada, Yumiko, Yuasa, Shigeki, Wakana, Shigeharu
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animal model; Animals; Animals, Newborn; Aspartic Acid - genetics; Attention - drug effects; Attention - physiology; Behavior; Behavior, Animal - physiology; Bromodeoxyuridine; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Central Nervous System Stimulants - pharmacology; Chromosome Mapping; d, l-Methylphenidate; Dark Adaptation - drug effects; Dark Adaptation - genetics; Developmental Disabilities - drug therapy; Developmental Disabilities - genetics; Disease Models, Animal; DNA Mutational Analysis; Dose-Response Relationship, Drug; Embryo, Mammalian; ENU mutagenesis; Ethylnitrosourea - pharmacology; Exploratory Behavior - physiology; Female; Gene Expression Regulation - genetics; Glycine - genetics; Homing Behavior - physiology; Male; Methylphenidate - pharmacology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Mutant Strains - genetics; Mice, Mutant Strains - physiology; Microscopy, Electron, Transmission; Mutagenesis - drug effects; Mutagens - pharmacology; Neocortex - embryology; Neocortex - growth & development; Neocortex - pathology; Neurodevelopmental disorder; Neurons - pathology; Neurons - ultrastructure; Phenotype; Time Factors; Tubulin - genetics; Tubulin alpha 1
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2011.11.002

[Display omitted] ► A hyperactive mutant mouse M101736 was isolated in ENU mutagenesis program. ► The mutant mouse carries a missense mutation in the Tuba1 gene. ► The heterozygote exhibited hyper activity and inattention to novel objects. ► Hyper activity and inattention were improved by methylphenidate administration. ► Disorganized structure of cerebral neocortex was observed in heterozygote. As part of the RIKEN large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis project, we screened mice with a dominant mutation that exhibited abnormal behavior using an open-field test and a home-cage activity test. We tested 495 male progeny of C57BL/6J males treated with ENU and untreated C3H/HeJ females using the open-field test and isolated behavioral mutant M101736, which exhibited a significant increase in spontaneous locomotor activity. We identified a missense mutation in the Tuba1 gene, which encodes the TUBA1 protein, and designated the mutant gene Tuba1 Rgsc1736 . This mutation results in an aspartic acid to glycine substitution in the TUBA1 protein. Detailed analyses revealed that Tuba1 Rgsc1736 heterozygotes exhibited inattention to novel objects and aberrant patterns of home-cage activity. The results of a behavioral pharmacological analysis using methylphenidate and morphological analyses of embryonic and adult brains suggested that Tuba1 Rgsc1736 is a novel animal model for neurodevelopmental disorders.