Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFC-mediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric disease-associated circRNA that regulates synaptic gene expression and cognitive flexibility.

中文翻译：

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一种与精神疾病相关的环状 RNA 控制突触基因的表达和认知。

尽管环状 RNA (circRNA) 在哺乳动物大脑中富集，但人们对它们在大脑功能和精神疾病中的潜在参与知之甚少。在这里，我们发现 circHomer1a 是一种在额叶皮层中大量表达的富含神经元的 circRNA，来源于 Homer 蛋白同源物 1 (HOMER1)，在前额叶皮层 (PFC) 和诱导的多能干细胞衍生的神经元培养物中均显着减少。精神分裂症（SCZ）和双相情感障碍（BD）患者。此外，circHomer1a 的改变与背外侧前额叶皮层 (DLPFC) 和眶额叶皮层 (OFC) 的 SCZ 发病年龄呈正相关。未观察到 SCZ 发病年龄与线性 HOMER1 mRNA 之间的相关性，其表达在 BD 和 SCZ 死后脑中大部分未改变。使用小鼠 PFC 中 circHomer1a 的体内 circRNA 特异性敲低，我们发现它调节了来自与突触可塑性和精神疾病有关的基因的许多替代 mRNA 转录物的表达。有趣的是，小鼠 OFC 体内 circHomer1a 敲低导致 OFC 介导的认知灵活性出现特定缺陷。最后，我们证明了神经元 RNA 结合蛋白 HuD 与 circHomer1a 结合并可以影响其在额叶皮层中的突触表达。总的来说，我们的数据揭示了一种新的与精神疾病相关的 circRNA，它调节突触基因表达和认知灵活性。体内 circHomer1a 在小鼠 OFC 中的敲低导致 OFC 介导的认知灵活性的特定缺陷。最后，我们证明了神经元 RNA 结合蛋白 HuD 与 circHomer1a 结合并可以影响其在额叶皮层中的突触表达。总的来说，我们的数据揭示了一种新的与精神疾病相关的 circRNA，它调节突触基因表达和认知灵活性。体内 circHomer1a 在小鼠 OFC 中的敲低导致 OFC 介导的认知灵活性的特定缺陷。最后，我们证明了神经元 RNA 结合蛋白 HuD 与 circHomer1a 结合并可以影响其在额叶皮层中的突触表达。总的来说，我们的数据揭示了一种新的与精神疾病相关的 circRNA，它调节突触基因表达和认知灵活性。