Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia.
Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia.
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DOI：
10.1038/s41598-018-31390-w
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发表时间：
2018-08-29
影响因子：
4.6
通讯作者：
Ozaki N
中科院分区：
文献类型：
--
作者：
Sobue A;Kushima I;Nagai T;Shan W;Kohno T;Aleksic B;Aoyama Y;Mori D;Arioka Y;Kawano N;Yamamoto M;Hattori M;Nabeshima T;Yamada K;Ozaki N
瑞林蛋白（RELN）是一种细胞外基质蛋白，在从胚胎神经元迁移到成年大脑中的树突棘形成等多个过程中发挥作用。遗传学研究结果表明，RELN与包括精神分裂症（SCZ）在内的精神疾病风险有关。我们先前在一名精神分裂症患者中发现了一种新的RELN外显子缺失。高分辨率拷贝数变异分析显示，这种缺失包括外显子52至58，它以与瑞林奥尔良突变（Relnrl - Orl）相似的方式截断了RELN。我们检查了该患者的临床特征，并证实其血清RELN水平降低。为了阐明RELN外显子缺失在精神分裂症中的病理生理作用，我们使用杂合的Relnrl - Orl/+小鼠进行了行为和神经化学分析。这些小鼠在焦虑、社交行为和运动学习方面表现出异常；抗精神病药物可改善运动学习缺陷。在Relnrl - Orl/+小鼠中，甲基苯丙胺诱导的活动亢进和多巴胺释放显著减少。此外，这些小鼠大脑中γ-氨基丁酸能标记物的水平降低。综上所述，我们的研究结果表明，RELN的外显子缺失在精神分裂症的病理生理过程中起病理作用，涉及多巴胺能和γ - 氨基丁酸能系统的功能变化。
Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.
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影响因子：
6.8
作者：
Arioka Y;Shishido E;Kubo H;Kushima I;Yoshimi A;Kimura H;Ishizuka K;Aleksic B;Maeda T;Ishikawa M;Kuzumaki N;Okano H;Mori D;Ozaki N
通讯作者：
Ozaki N
影响因子：
5.3
作者：
DArcangelo, G;Nakajima, K;Curran, T
通讯作者：
Curran, T
影响因子：
4.2
作者：
Bullock, W. Michael;Bolognani, Federico;Perrone-Bizzozero, Nora I.
通讯作者：
Perrone-Bizzozero, Nora I.
影响因子：
2.7
作者：
Alkam, Tursun;Kim, Hyoung-Chun;Nabeshima, Toshitaka
通讯作者：
Nabeshima, Toshitaka
影响因子：
4.7
作者：
Folsom TD;Fatemi SH
通讯作者：
Fatemi SH