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.

中文翻译：

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Claudin-5 的剂量依赖性表达是精神分裂症的调节因子。

精神分裂症是一种神经发育障碍，影响高达 1% 的普通人群。各种基因显示出与精神分裂症的关联，并且与紧密连接蛋白 claudin-5 的名义关联非常弱，此前已被确定。Claudin-5 在形成血脑屏障 (BBB) 一部分的内皮细胞中表达。此外，精神分裂症发生在 30% 的 22q11 缺失综合征 (22q11DS) 个体中，这是一个 claudin-5 基因单倍体不足的人群。在这里，我们显示 claudin-5 基因中的一个变体与 22q11DS 中的精神分裂症弱相关，导致内皮细胞中表达的 claudin-5 减少了 75%。我们还表明，靶向腺相关病毒介导的小鼠大脑中 claudin-5 的抑制会导致局部 BBB 破坏和行为改变。使用可诱导的“击倒”小鼠模型，我们通过显示学习和记忆、焦虑样行为和感觉运动门控障碍的独特行为表型进一步将 Claudin-5 抑制与精神病联系起来。此外，这些动物在 claudin-5 抑制 3-4 周后出现癫痫发作并死亡，这加强了 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在体外和体内呈剂量依赖性地增加 claudin-5 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、不连续表达。一起，