Mice lacking the kf-1 gene exhibit increased anxiety- but not despair-like behavior

• Published in: Frontiers in behavioral neuroscience Vol. 2; p. 4
• Main Authors: Tsujimura, Atsushi, Matsuki, Masato, Takao, Keizo, Yamanishi, Kiyofumi, Miyakawa, Tsuyoshi, Hashimoto-Gotoh, Tamotsu
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 01.01.2008; Frontiers Media S.A
• Subjects: Animal models; Anxiety; Behavior; Behavioral despair; Central nervous system; Cerebellum; Cerebral cortex; Cortex (frontal); Depression; Gene expression; Gene targeting; Genetic engineering; knockout mouse; Locomotion; Mental depression; Mental disorders; Molecular modelling; Mutation; Neuroscience; Open-field behavior; Pathogenesis; Patients; Physiology; Proteins; Recombination; Schizophrenia; Ubiquitin; ubiquitin ligase; Ubiquitin-protein ligase; Ubiquitination; Japan; ubiquitin ligase; anxiety; depression; schizophrenia; knockout mouse
• ISSN: 1662-5153; 1662-5153
• DOI: 10.3389/neuro.08.004.2008

KF-1 was originally identified as a protein encoded by human gene with increased expression in the cerebral cortex of a patient with Alzheimer's disease. In mouse brain, kf-1 mRNA is detected predominantly in the hippocampus and cerebellum, and kf-1 gene expression is elevated also in the frontal cortex of rats after chronic antidepressant treatments. KF-1 mediates E2-dependent ubiquitination and may modulate cellular protein levels as an E3 ubiquitin ligase, though its target proteins are not yet identified. To elucidate the role of kf-1 in the central nervous system, we generated kf-1 knockout mice by gene targeting, using Cre-lox recombination. The resulting kf-1(-/-) mice were normal and healthy in appearance. Behavioral analyses revealed that kf-1(-/-) mice showed significantly increased anxiety-like behavior compared with kf-1(+/+) littermates in the light/dark transition and elevated plus maze tests; however, no significant differences were observed in exploratory locomotion using the open field test or in behavioral despair using the forced swim and tail suspension tests. These observations suggest that KF-1 suppresses selectively anxiety under physiological conditions probably through modulating protein levels of its unknown target(s). Interestingly, kf-1(-/-) mice exhibited significantly increased prepulse inhibition, which is usually reduced in human schizophrenic patients. Thus, the kf-1(-/-) mice provide a novel animal model for elucidating molecular mechanisms of psychiatric diseases such as anxiety/depression, and may be useful for screening novel anxiolytic/antidepressant compounds.