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Dysregulation of schizophrenia‐related aquaporin 3 through disruption of paranode influences neuronal viability
Author(s) -
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
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14553
Subject(s) - conditional gene knockout , knockout mouse , biology , microbiology and biotechnology , myelin , gene knockdown , neuroscience , central nervous system , gene , genetics , phenotype
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 ( NF 155) 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 NF 155 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 NF 155 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 ( AQP 3 ) was significantly reduced in NF 155 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 AQP 3 in SCZ patients, suggesting a correlation between abnormal AQP 3 expression and SCZ . To determine if AQP 3 over‐expression in NF 155 conditional knockout mice influences neuronal function, we performed adeno‐associated virus ( AAV )‐mediated over‐expression of AQP 3 in the motor cortex of mice and found a significant increase in caspase 3‐dependent neuronal apoptosis in AQP 3 ‐transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP 3 expression, which is associated with paranodal disruption.