Human mood disorders risk gene synaptotagmin14 affects mania-like behaviors in mice

Major depressive disorder (MDD) and bipolar disorder (BD) are the most prevalent mood disorders and cause considerable burden worldwide. Compelling evidence suggests a pronounced overlap between these two diseases in clinical symptoms, treatment strategies, and genetic etiology. Here we use a BD GWAS (1822 cases and 4650 controls) and a MDD GWAS (5303 cases and 5337 controls) of Han Chinese origin to investigate their shared genetic basis, followed by exploration of the underlying mechanisms. The lead SNP in the Han Chinese meta-analysis, rs126277 at the 1q32.2 locus, also exhibited nominal associations with mood disorders as well as several sub-clinical phenotypes (e.g., mania) related to mood disorders (UK biobank samples) in European populations. Bulk tissue and single-cell eQTL studies suggest that the risk G-allele of rs126277 predicted lower SYT14 mRNA expression in human brain tissues and cells, indicating possible involvement of this gene in mood disorders. We generated mice lacking Syt14 (Syt14/) and mice with insufficient expression of Syt14 in the hippocampus (Syt14-KD). We found that depletion of Syt14 resulted in mania-like behaviors including hyperactivity and anti-depressive behaviors, resembling aspects of mood disorders. We also confirmed that deficiency of this gene in the hippocampus was sufficient to induce hyperactivity in the mice. RNA-sequencing analyses of the hippocampus of Syt14/ mice revealed significant upregulation of Per1 as well as downregulation of Slc7a11 and Ptprb. Ultrastructural analyses showed significant alteration of the number of vesicles within 50 nm to the active zone and the width of synaptic cleft in the ventral hippocampus of Syt14/ mice compared with control mice. And Syt14/ mice exhibit aberrant glutamate signaling patterns in the hippocampus. Overall, we have identified a novel mood disorder risk gene SYT14, and confirmed its impact on mania-like behaviors and essential roles in synaptic function. While the current study provides clues for the pathological mechanisms of mood disorders, further investigations elucidating the detailed mechanisms by which SYT14 regulates mood disorders-related traits are needed. To investigate the function of Syt14 in mood disorder and motor coordination, we procured the hippocampus and cerebellum tissues from three Syt14 knockout (Syt14-/-) mice and three wild-type (Syt14+/+) mice. Subsequently, we conducted a comprehensive gene expression profiling analysis, leveraging the data derived from RNA sequencing (RNA-seq) of these tissues. Comparative gene expression profiling analysis of RNA-seq data for Syt14-/- mice and Syt14 +/+ mice.重度抑郁症（Major depressive disorder, MDD）与双相情感障碍（bipolar disorder, BD）是全球范围内最为流行的心境障碍，可造成沉重的疾病负担。大量确凿证据表明，这两种疾病在临床症状、治疗策略以及遗传病因学方面存在显著的重叠。本研究利用汉族人群来源的双相情感障碍全基因组关联研究（Genome-Wide Association Study, GWAS，1822例病例与4650例对照）与重度抑郁症全基因组关联研究（Genome-Wide Association Study, GWAS，5303例病例与5337例对照），探究二者共有的遗传基础，并进一步探索其潜在分子机制。 汉族人群荟萃分析中的最显著单核苷酸多态性（Single Nucleotide Polymorphism, SNP）——1q32.2位点的rs126277，在欧洲人群的英国生物样本库（UK Biobank）样本中，同样与心境障碍及若干与心境障碍相关的亚临床表型（如躁狂）表现出边缘显著的关联。 整体组织与单细胞表达数量性状位点（expression Quantitative Trait Locus, eQTL）研究显示，rs126277的风险等位基因G在人类脑组织与细胞中可预测较低的SYT14信使RNA（messenger RNA, mRNA）表达水平，提示该基因可能参与心境障碍的发病过程。 我们构建了Syt14敲除小鼠（Syt14⁻/⁻）以及海马体中Syt14表达不足的小鼠（Syt14-KD）。研究发现，Syt14的缺失会导致类似躁狂的行为表型，包括活动过度与抗抑郁样行为，这与心境障碍的部分特征相符。我们同时证实，海马体中该基因的缺失足以引发小鼠的活动过度现象。 对Syt14⁻/⁻小鼠海马体的RNA测序（RNA-sequencing, RNA-seq）分析显示，Per1基因出现显著上调，而Slc7a11与Ptprb基因则出现显著下调。超微结构分析显示，与对照小鼠相比，Syt14⁻/⁻小鼠腹侧海马体中，活性区50nm范围内的囊泡数量以及突触间隙宽度均发生显著改变。此外，Syt14⁻/⁻小鼠海马体中存在异常的谷氨酸信号传导模式。 综上，本研究鉴定出一个全新的心境障碍风险基因SYT14，并证实其对躁狂样行为的影响以及在突触功能中的关键作用。尽管本研究为心境障碍的病理机制提供了线索，但仍需进一步研究以阐明SYT14调控心境障碍相关表型的具体分子机制。 为探究Syt14在心境障碍与运动协调中的功能，我们从3只Syt14敲除小鼠（Syt14⁻/⁻）与3只野生型小鼠（Syt14⁺/⁺）中获取了海马体与小脑组织。随后，我们基于这些组织的RNA测序数据，开展了全面的基因表达谱分析，并完成了Syt14⁻/⁻与Syt14⁺/⁺小鼠的RNA测序数据的对比基因表达谱分析。