Role of Psychiatric Disease-associated Circular RNAs in Neuronal Function and Cognition

项目摘要 精神分裂症（SCZ）和双相情感障碍（BD）是异质性精神障碍，具有严重的精神障碍症状。 社会经济影响和未知的发病机制。环状RNA（circRNA）是一类新的非- 来自蛋白质外显子和内含子的反向剪接和共价连接的编码RNA- 编码基因，但缺乏翻译成蛋白质的能力。最近的研究表明， circRNA在大脑中相对富集，优先从大脑可塑性相关的神经元中产生。 基因，并在树突和突触丰富。然而，人们对它的功能知之甚少。 人类大脑中的circRNA及其在神经精神疾病中的潜在参与。在这里，我们进行了 在一个大型队列的人类死后大脑中， SCZ和BD发现了一个差异表达的circRNA的子集，这些circRNA是由已知的 与突触可塑性和神经元兴奋性有关。我们建议研究进化的功能， 保守的，神经元富集的circRNA，circHomer 1，它在前额叶皮层（PFC）中减少， BD和SCZ死后脑和患者来源的神经元培养物。我们假设 circHomer 1通过抑制其表达来抑制突触传递和神经元兴奋性 和可塑性相关的Homer蛋白同系物1长同种型B（HOMER 1 B）mRNA的突触定位， 从而破坏PFC功能。我们打算敲低circHomer 1在两个诱导性多能细胞中的表达， 干细胞（iPSC）衍生的神经元培养物和小鼠PFC，并检查其在神经元功能和 精神疾病相关行为。我们将通过三个具体目标来测试我们的假设：1）测试假设 在人类PFC中，circHomer 1和HOMER 1B mRNA水平以细胞特异性方式发生差异性改变， 和来自精神疾病患者的iPSC衍生的神经元培养物。2)测试的假设 circHomer 1通过抑制HOMER 1B定位来调节突触功效和神经元兴奋性。第三章 验证PFC中circHomer 1缺陷影响神经元放电、认知灵活性和认知功能的假设。 感觉运动门控

PROJECT SUMMARY Schizophrenia (SCZ) and Bipolar disorder (BD) are heterogeneous psychiatric disorders with severe socioeconomic impacts and unknown pathogenesis. Circular RNAs (circRNAs) are a novel category of non- coding RNAs that are derived from the back-splicing and covalent joining of exons and introns of protein- coding genes, yet lack the capacity to become translated into protein. Recent studies have suggested that circRNAs are relatively enriched in the brain, are preferentially generated from brain plasticity-associated genes, and are abundant in dendrites and synapses. However, very little is known about the function of circRNAs in the human brain and their potential involvement in neuropsychiatric disease. Here we carried out systematic profiling of circRNA expression in a large cohort of human postmortem brains from subjects with SCZ and BD and uncovered a subset of differentially expressed circRNAs produced from genes with known links to synaptic plasticity and neuronal excitability. We propose to study the function of the evolutionary conserved, neuronal-enriched circRNA, circHomer1, which is reduced in both the prefrontal cortex (PFC) of both BD and SCZ postmortem brains and in patient-derived neuronal cultures. We hypothesize that circHomer1 inhibits glutamatergic synaptic transmission and neuronal excitiability via inhibiting the expression and synaptic localization of plasticity-related Homer protein homolog 1 long isoform B (HOMER1B) mRNA, thereby disrupting PFC functions. We intend to knockdown circHomer1 expression in both induced pluripotent stem cell (iPSC)-derived neuronal cultures and mouse PFC and examine its role in neuronal fuction and psychiatric disease-related behavior. We will test our hypothesis via three specific aims: 1) Test the hypothesis that circHomer1 and HOMER1B mRNA levels are differentially altered in a cell-specific manner in human PFC and iPSC-derived neuronal cultures from patients with psychiatric disease. 2) Test the hypothesis that circHomer1 regulates synaptic efficacy and neuronal excitability through inhibition of HOMER1B localization. 3) Test the hypothesis that circHomer1 deficits in the PFC influence neuronal firing, cognitive flexibility, and sensorimotor gating.