Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.
Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.
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DOI：
10.1038/mp.2017.156
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发表时间：
2018-11
影响因子：
11
通讯作者：
Campbell M
中科院分区：
文献类型：
--
作者：
Greene C;Kealy J;Humphries MM;Gong Y;Hou J;Hudson N;Cassidy LM;Martiniano R;Shashi V;Hooper SR;Grant GA;Kenna PF;Norris K;Callaghan CK;Islam MD;O'Mara SM;Najda Z;Campbell SG;Pachter JS;Thomas J;Williams NM;Humphries P;Murphy KC;Campbell M
精神分裂症是一种神经发育障碍，影响高达1%的一般人群。各种基因显示与精神分裂症和紧密连接蛋白，claudin-5，一个非常弱的名义关联，先前已被确定。紧密连接蛋白-5在形成血脑屏障（BBB）的一部分的内皮细胞中表达。此外，精神分裂症发生在30%的22 q11缺失综合征（22 q11 DS）患者中，这是一个claudin-5基因单倍不足的人群。在这里，我们表明，在claudin-5基因的变异是弱相关的精神分裂症在22 q11 DS，导致75%的少表达claudin-5在内皮细胞。我们还表明，靶向腺相关病毒介导的小鼠大脑中claudin-5的抑制导致局部BBB破坏和行为变化。使用可诱导的“敲低”小鼠模型，我们进一步通过一种独特的行为表型将claudin-5抑制与精神病联系起来，这种行为表型显示出学习和记忆、焦虑样行为和感觉运动门控的损伤。此外，这些动物在claudin-5抑制3-4周后发生癫痫发作并死亡，加强了claudin-5在正常神经功能中的关键作用。最后，我们发现抗精神病药物剂量依赖性地增加claudin-5在体外和体内的表达，而与年龄匹配的对照组相比，在精神分裂症患者死后的大脑中观察到claudin-5的异常，不连续的表达。总之，这些数据表明，血脑屏障破坏可能是精神分裂症发展中的一个修饰因素，直接靶向血脑屏障的药物可能为治疗这种疾病提供新的治疗机会。
Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible ‘knockdown’ mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3–4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin−5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.
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