Oligodendroglial isoforms of ANK3 and their role in CNS function

新摘要：包括精神分裂症、双相情感障碍和自闭症在内的复杂神经精神疾病的病因仍然知之甚少。重要的是，许多神经精神障碍具有高度的遗传性，这表明潜在的原因是遗传而不是环境。大型全基因组关联研究(GWAS)已经开始揭示与这些疾病相关的特定基因。其中，ANK3(AnkyrinG(AnkG)的编码基因)可能与躁郁症、精神分裂症和自闭症有关。然而，ANK3变异如何导致这些疾病仍不清楚。重要的是，仅在少突胶质细胞中发现的含有新的外显子(称为BDEX)的ANK3剪接变异体可能对双相情感障碍具有保护作用。我们之前在髓鞘少突胶质细胞的副节点中发现了AnkG，在早期发育过程中，AnkG在结旁连接的及时组装中发挥作用。然而，少突胶质细胞AnkG在老年小鼠中的功能仍不清楚。我们将确定AnkG在少突胶质细胞中的功能，更具体地说，BDEX的功能。我们将确定含有BDEX的AnkG在少突胶质细胞中的准确位置。我们将使用功能丧失和功能获得的小鼠模型来研究少突胶质细胞ANK3变体在大脑中的作用。我们将检查结节和旁阳极结构、髓鞘、有髓轴突的生理和行为。总之，这些研究将开始揭示少突胶质AnkG和BDEX AnkG的作用，并可能揭示ANK3相关神经精神疾病的分子病理生理学。

New Abstract: The causes of complex neuropsychiatric disorders including schizophrenia, bipolar disorder, and autism remain poorly understood. Importantly, many neuropsychiatric disorders are highly heritable, indicating the underlying cause is genetic rather than environmental. Large genome-wide association studies (GWAS) have begun to reveal specific genes associated with these disorders. Among these, ANK3 (the gene coding for AnkyrinG (AnkG)) is potentially associated with bipolar disorder, schizophrenia, and autism. However, how ANK3 variants contribute to these disorders remains unknown. Importantly a loss-of-function ANK3 splice variant containing a novel exon (termed BDex) found only in oligodendrocytes may be protective against bipolar disease. We previously found AnkG in paranodes of myelinating oligodendrocytes, where it functions in the timely assembly of paranodal junctions during early development. However, the function of oligodendroglial AnkG in older mice remains unknown. We will determine the function of AnkG in oligodendrocytes, and more specifically the function of BDex. We will define the precise location of BDex-containing AnkG in oligodendrocytes. We will use loss-of-function and gain-of-function mouse models to investigate the role of oligodendroglial ANK3 variants in the brain. We will examine node and paranode structure, myelin, myelinated axon physiology, and behavior. Together, these studies will begin to uncover the role of oligodendroglial AnkG and BDex AnkG, and may reveal insights into the molecular pathophysiology of ANK3-associated neuropsychiatric disorders.