Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype.
Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype.
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DOI：
10.1371/journal.pbio.0050297
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发表时间：
2007-11
期刊：
影响因子：
9.8
通讯作者：
Yoshikawa, Takeo
中科院分区：
文献类型：
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作者：
Watanabe, Akiko;Toyota, Tomoko;Owada, Yuji;Hayashi, Takeshi;Iwayama, Yoshimi;Matsumata, Miho;Ishitsuka, Yuichi;Nakaya, Akihiro;Maekawa, Motoko;Ohnishi, Tetsuo;Arai, Ryoichi;Sakurai, Katsuyasu;Yamada, Kazuo;Kondo, Hisatake;Hashimoto, Kenji;Osumi, Noriko;Yoshikawa, Takeo
前脉冲抑制（PPI）缺陷是精神分裂症的生物学标志。为了阐明控制PPI的机制，我们对1,010只F2小鼠进行了数量性状基因座（QTL）分析，这些小鼠是通过将显示高PPI的C57 BL/6（B6）动物与显示低PPI的C3 H/He（C3）动物杂交而获得的。我们检测到六个主要位点的PPI，六声惊吓反应，和四个潜伏期的响应峰值，其中一些是性别依赖性。染色体10-QTL上的一个有希望的候选者是Fabp 7（脂肪酸结合蛋白7，脑），一个与N-甲基-D-天冬氨酸（NMDA）受体功能连接并在星形胶质细胞中表达的基因。Fabp 7缺陷小鼠表现出PPI降低和惊吓反应潜伏期缩短，这是QTL提出的典型效应。定量互补试验支持Fabp 7作为一个潜在的PPI-QTL基因，特别是在雄性小鼠。Fabp 7的破坏在体内减弱神经发生。人类FABP 7在精神分裂症患者的大脑中表现出改变的表达，并与精神分裂症有遗传关联，当样本按性别划分时，这在男性中都很明显。这些结果表明，FABP 7起着一个新的和关键的作用，连接NMDA，神经发育，神经胶质理论的精神分裂症病理和PPI内表型，在男性中具有较大或明显的影响。我们还讨论了胎儿编程的角度来看的结果。对意外的、强烈的惊吓刺激的惊吓反应可以被紧接在前的低强度刺激所抑制，从而引起很少的行为反应。这种现象被称为前脉冲抑制（PPI），在所有测试的哺乳动物中都观察到，并被认为反映了生物体中的感觉-运动门控功能。PPI在人类精神分裂症中减少，提高了PPI可能作为该疾病的潜在生物标志物的可能性。一旦在低等动物中确定了调节PPI的基因，预计人类直系同源物将是精神分裂症的强有力的候选基因。在这项研究中，我们首先进行了遗传解剖小鼠PPI使用数量性状基因座分析，检测染色体区域窝藏致病基因。进一步的分析，包括那些敲除小鼠，使我们能够确定一个潜在的致病基因，Fabp 7（脂肪酸结合蛋白7，大脑），一个伴侣的必需脂肪酸二十二碳六烯酸。人类研究表明，FABP 7基因与精神分裂症适度相关，并且在精神分裂症患者的大脑中转录表达水平上调。从这些结果中，我们提出，FABP 7蛋白介导的发育中的大脑中的基本脂质代谢紊乱可能是精神分裂症的发展的一个危险因素，在男性中具有更大的影响。前脉冲抑制被认为是精神分裂症的一种生物学特征，寻找前脉冲抑制的相关基因已经揭示了编码必需脂肪酸结合蛋白的基因。
Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. Fabp7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene, particularly in male mice. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming. A startle response to an unexpected, strong startling stimulus can be suppressed by an immediately preceding low-intensity stimulus, thereby eliciting little behavioral response. This phenomenon, called prepulse inhibition (PPI), has been observed in all mammals tested and is thought to reflect sensory-motor gating functions in organisms. PPI is diminished in human schizophrenia, raising the possibility that PPI might serve as a potential biological marker for the disease. Once the genes regulating PPI in lower animals are identified, it is expected that the human orthologs will be strong candidate genes for schizophrenia. In this study, we first performed a genetic dissection of mouse PPI using quantitative trait loci analysis, which detects chromosomal regions harboring causative genes. Further analyses including those of knockout mice, allowed us to identify one potential causative gene, Fabp7 (fatty acid binding protein 7, brain), a chaperon for the essential fatty acid docosahexaenoic acid. Human studies showed that the FABP7 gene is modestly associated with schizophrenia and that transcript expression levels are up-regulated in schizophrenic brains. From these results, we propose that a FABP7 protein-mediated disturbance of essential lipid metabolism in developing brains may be one risk factor in the development of schizophrenia, with a greater effect in males. The search for responsible genes for prepulse inhibition, a measure deemed to be a biological trait in schizophrenia, has exposed a gene encoding essential fatty acid-binding protein.