title: Mice lacking the kf-1 gene exhibit increased anxiety- but not despair-like behavior.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, RINDG, Kyoto Prefectural University of Medicine Kyoto, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tsujimura
authors.forename: Masato
authors.initials: M
authors.lastname: Matsuki
authors.forename: Keizo
authors.initials: K
authors.lastname: Takao
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamanishi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Hashimoto-Gotoh