Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsusima, Aobaku, Sendai, Miyagi 981-8558, Japan.
J Biol Chem. 2011 May 27;286(21):18434-43. doi: 10.1074/jbc.M110.172536. Epub 2011 Apr 6.
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.
先前，我们曾报道过，α1,6-岩藻糖基转移酶（Fut8）缺陷型（Fut8(-/-)）小鼠肺部出现类肺气肿改变，且由于 TGF-β1 和 EGF 受体的失调以及整合素的异常激活，出现严重的生长迟缓。为了研究 α1,6-岩藻糖基化在 Fut8 高表达的脑组织中的作用，我们结合神经学和行为学测试，对 Fut8(-/-)小鼠进行了研究。Fut8(-/-)小鼠表现出多种与精神分裂症表型一致的行为异常。与野生型（Fut8(+/+)）和杂合型（Fut8(+/-)）小鼠相比，Fut8(-/-)小鼠的运动能力增强。特别是 Fut8(-/-)小鼠在新环境中表现出剧烈的跳跃行为。Y 迷宫测试表明 Fut8(-/-)小鼠的工作记忆能力受损。此外，Fut8(-/-)小鼠还表现出前脉冲抑制（PPI）缺陷。有趣的是，尽管 Fut8(+/+)和 Fut8(+/-)小鼠在正常条件下的 PPI 测试中没有显著差异，但 Fut8(+/-)小鼠在暴露于束缚应激后表现出 PPI 受损。这一结果表明 Fut8 的表达降低可能是精神分裂症和相关疾病的一个合理原因。Fut8(-/-)小鼠的纹状体和伏隔核中的 5-羟色胺代谢物水平均显著降低。同样，抗精神病药物氟哌啶醇（可拮抗多巴胺能和 5-羟色胺能受体）的治疗也显著减少了跳跃行为。本研究首次明确表明，α1,6-岩藻糖基化在大脑中发挥重要作用，并且可能与类精神分裂症行为有关。因此，本研究的结果为精神分裂症和相关疾病的潜在机制提供了新的见解。
