Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with unknown etiology. Recent experimental evidences suggest the contribution of non-coding RNAs (ncRNAs) in the pathophysiology of ASD. In this work, we aimed to investigate the expression profile of the ncRNA class of circular RNAs (circRNAs) in the hippocampus of the BTBR T + tf/J (BTBR) mouse model and age-matched C57BL/6J (B6) mice. Alongside, we analyzed BTBR hippocampal gene expression profile to evaluate possible correlations between the differential abundance of circular and linear gene products. From RNA sequencing data, we identified circRNAs highly modulated in BTBR mice. Thirteen circRNAs and their corresponding linear isoforms were validated by RT-qPCR analysis. The BTBR-regulated circCdh9 was better characterized in terms of molecular structure and expression, highlighting altered levels not only in the hippocampus, but also in the cerebellum, prefrontal cortex, and amygdala. Finally, gene expression analysis of the BTBR hippocampus pinpointed altered biological and molecular pathways relevant for the ASD phenotype. By comparison of circRNA and gene expression profiles, we identified 6 genes significantly regulated at either circRNA or mRNA gene products, suggesting low overall correlation between circRNA and host gene expression. In conclusion, our results indicate a consistent deregulation of circRNA expression in the hippocampus of BTBR mice. ASD-related circRNAs should be considered in functional studies to identify their contribution to the etiology of the disorder. In addition, as abundant and highly stable molecules, circRNAs represent interesting potential biomarkers for autism.

中文翻译：

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自闭症谱系障碍的 BTBR 小鼠模型中海马环状 RNA 的差异表达。

自闭症谱系障碍（ASD）是一种病因不明的异质性神经发育疾病。最近的实验证据表明非编码 RNA (ncRNA) 在 ASD 的病理生理学中的作用。在这项工作中，我们旨在研究 BTBR T + tf/J (BTBR) 小鼠模型和年龄匹配的 C57BL/6J (B6) 小鼠海马中 ncRNA 类环状 RNA (circRNA) 的表达谱。此外，我们分析了 BTBR 海马基因表达谱，以评估环状和线性基因产物的差异丰度之间可能存在的相关性。从 RNA 测序数据中，我们确定了 BTBR 小鼠中高度调节的 circRNA。通过 RT-qPCR 分析验证了 13 个 circRNA 及其相应的线性异构体。BTBR 调节的 circCdh9 在分子结构和表达方面具有更好的特征，不仅在海马体中，而且在小脑、前额叶皮层和杏仁核中都显示出水平的变化。最后，BTBR 海马的基因表达分析确定了与 ASD 表型相关的改变的生物学和分子途径。通过比较 circRNA 和基因表达谱，我们确定了 6 个基因在 circRNA 或 mRNA 基因产物中受到显着调控，表明 circRNA 与宿主基因表达之间的总体相关性较低。总之，我们的结果表明 BTBR 小鼠海马中 circRNA 表达的一致失调。在功能研究中应考虑 ASD 相关的 circRNA，以确定它们对疾病病因的贡献。此外，