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.
Bipolar disorder (BD) is a complex, heritable disease with poorly understood etiology. We found an ANK3 loss of function variant, expressed in oligodendrocytes, that is strongly protective against BD. We will determine the function and role of oligodendroglial isoforms of ANK3 and their contributions to the oligodendrocyte function and the pathogenesis of BD.