title: Alpha1,6-fucosyltransferase-deficient mice exhibit multiple behavioral abnormalities associated with a schizophrenia-like phenotype: importance of the balance between the dopamine and serotonin systems.
abstract: Previously, we reported that α1,6-fucosyltransferase (Fut8)-deficient (Fut8(-/-)) mice exhibit emphysema-like changes in the lung and severe growth retardation due to dysregulation of TGF-β1 and EGF receptors and to abnormal integrin activation, respectively. To study the role of α1,6-fucosylation in brain tissue where Fut8 is highly expressed, we examined Fut8(-/-) mice using a combination of neurological and behavioral tests. Fut8(-/-) mice exhibited multiple behavioral abnormalities consistent with a schizophrenia-like phenotype. Fut8(-/-) mice displayed increased locomotion compared with wild-type (Fut8(+/+)) and heterozygous (Fut8(+/-)) mice. In particular, Fut8(-/-) mice showed strenuous hopping behavior in a novel environment. Working memory performance was impaired in Fut8(-/-) mice as evidenced by the Y-maze tests. Furthermore, Fut8(-/-) mice showed prepulse inhibition (PPI) deficiency. Intriguingly, although there was no significant difference between Fut8(+/+) and Fut8(+/-) mice in the PPI test under normal conditions, Fut8(+/-) mice showed impaired PPI after exposure to a restraint stress. This result suggests that reduced expression of Fut8 is a plausible cause of schizophrenia and related disorders. The levels of serotonin metabolites were significantly decreased in both the striatum and nucleus accumbens of the Fut8(-/-) mice. Likewise, treatment with haloperidol, which is an antipsychotic drug that antagonizes dopaminergic and serotonergic receptors, significantly reduced hopping behaviors. The present study is the first to clearly demonstrate that α1,6-fucosylation plays an important role in the brain, and that it might be related to schizophrenia-like behaviors. Thus, the results of the present study provide new insights into the underlying mechanisms responsible for schizophrenia and related disorders.
authors.affiliation: Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsusima, Aobaku, Sendai, Miyagi 981-8558, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Fukuda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Natsumi
authors.initials: N
authors.lastname: Okayasu
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kameyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Onogi
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakagawasai
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Kurosawa
authors.forename: Yan
authors.initials: Y
authors.lastname: Hao
authors.forename: Tomoya
authors.initials: T
authors.lastname: Isaji
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tadano
authors.forename: Hisashi
authors.initials: H
authors.lastname: Narimatsu
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Jianguo
authors.initials: J
authors.lastname: Gu
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal; D001921:Brain / Q000201:enzymology*; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D005647:Fucosyltransferases; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D012559:Schizophrenia / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D012701:Serotonin; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase; D006220:Haloperidol; D004298:Dopamine