A Spontaneous Point Mutation Produces Monoamine Oxidase A/B Knock-out Mice with Greatly Elevated Monoamines and Anxiety-like Behavior

• Published in: The Journal of biological chemistry 2004-09, Vol.279 (38), p.39645-39652
• Main Authors: Chen, Kevin, Holschneider, Daniel P., Wu, Weihua, Rebrin, Igor, Shih, Jean C.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Anxiety - genetics; Anxiety - metabolism; Anxiety - physiopathology; Base Sequence; Behavior, Animal - physiology; Biogenic Monoamines - metabolism; Codon, Nonsense; Exons; Female; Male; Mice; Mice, Knockout; Molecular Sequence Data; Monoamine Oxidase - genetics; Monoamine Oxidase - metabolism; Phenotype; Point Mutation; RNA, Messenger - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M405550200

A spontaneous monoamine oxidase A (MAO A) mutation (A863T) in exon 8 introduced a premature stop codon, which produced MAO A/B double knock-out (KO) mice in a MAO B KO mouse colony. This mutation caused a nonsense-mediated mRNA decay and resulted in the absence of MAO A transcript, protein, and catalytic activity and abrogates a DraI restriction site. The MAO A/B KO mice showed reduced body weight compared with wild type mice. Brain levels of serotonin, norepinephrine, dopamine, and phenylethylamine increased, and serotonin metabolite 5-hydroxyindoleacetic acid levels decreased, to a much greater degree than in either MAO A or B single KO mice. Observed chase/escape and anxiety-like behavior in the MAO A/B KO mice, different from MAO A or B single KO mice, suggest that varying monoamine levels result in both a unique biochemical and behavioral phenotype. These mice will be useful models for studying the molecular basis of disorders associated with abnormal monoamine neurotransmitters.