α1,6-Fucosyltransferase-deficient Mice Exhibit Multiple Behavioral Abnormalities Associated with a Schizophrenia-like Phenotype

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. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.