Dysregulation of schizophrenia‐related aquaporin 3 through disruption of paranode influences neuronal viability

• Published in: Journal of neurochemistry Vol. 147; no. 3; pp. 395 - 408
• Main Authors: Kunisawa, Kazuo, Shimizu, Takeshi, Kushima, Itaru, Aleksic, Branko, Mori, Daisuke, Osanai, Yasuyuki, Kobayashi, Kenta, Taylor, Anna M., Bhat, Manzoor A., Hayashi, Akiko, Baba, Hiroko, Ozaki, Norio, Ikenaka, Kazuhiro
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2018
• Subjects: Ablation; Animals; Apoptosis; Aquaporin 3; Aquaporin 3 - metabolism; Aquaporins; Axons; Axons - metabolism; Axons - pathology; Caspase; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase-3; Cell Adhesion Molecules - biosynthesis; Cell Adhesion Molecules - genetics; Cell Survival; Conduction; Contactin; Copy number; copy number variant; Cortex (motor); Dependovirus - genetics; Disruption; DNA Copy Number Variations; Etiology; Female; Gene Duplication; Gene Expression; Male; Mental disorders; Mice; Mice, Knockout; Mice, Transgenic; Motor Cortex - metabolism; multiple sclerosis; Nerve Growth Factors - biosynthesis; Nerve Growth Factors - genetics; neurofascin155; Neuronal-glial interactions; Neurons - metabolism; Neurons - pathology; Oligodendrocytes; paranodal junction; Proteins; Retina; Ribonucleic acid; RNA; Rodents; Schizophrenia; Schizophrenia - metabolism; Schizophrenia - pathology; Sulfotransferase; Viability; Viruses; copy number variant; aquaporin 3; paranodal junction; schizophrenia; neurofascin155; multiple sclerosis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14553

Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST‐KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over‐expression in NF155 conditional knockout mice influences neuronal function, we performed adeno‐associated virus (AAV)‐mediated over‐expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3‐dependent neuronal apoptosis in AQP3‐transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption. The aquaporin 3 was related to the list of genes identified with copy number variations of schizophrenia, suggesting a correlation between abnormal aquaporin 3 expression and schizophrenia. We found that aquaporin 3 was sensitive to paranodal abnormalities. We further showed that dysregulation of aquaporin 3 expression through disruption of paranode affected neuronal viability. Further understanding of aquaporin 3 function may provide new insights into the etiology of schizophrenia caused by oligodendrocyte abnormalities and potential therapeutic approaches.