TY - JOUR
T1 - Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability
AU - Kunisawa, Kazuo
AU - Shimizu, Takeshi
AU - Kushima, Itaru
AU - Aleksic, Branko
AU - Mori, Daisuke
AU - Osanai, Yasuyuki
AU - Kobayashi, Kenta
AU - Taylor, Anna M.
AU - Bhat, Manzoor A.
AU - Hayashi, Akiko
AU - Baba, Hiroko
AU - Ozaki, Norio
AU - Ikenaka, Kazuhiro
N1 - Funding Information:
This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas ‘Glial Assembly’ (25117001) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); by AMED under grant No. JP18dm0107087; and No.JP18dm0207005. M.A.B. is supported by grants from the NIH NIGMS GM063074, National Multiple Sclerosis Society, and the Zachry Foundation (M.A.B). A.M.T. is supported by a NIH NINDS Postdoctoral Fellowship (F32NS092448). Confocal images were acquired at the Spectrography and Bioimaging Facility, National Institute for Basic Biology Core Research Facilities. We thank Dr H. Sano, Dr N. Hatanaka, and Prof. A. Nambu (National Institute for Physiological Sciences, Japan) for technical advice on injections into the motor cortex. We also thank our laboratory members for helpful discussions. The authors declare a conflict of interest that Kazuhiro Ikenaka is the current president of the ISN.
Funding Information:
This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas ‘Glial Assembly’ (25117001) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); by AMED under grant No. JP18dm0107087; and No.JP18dm0207005. M.A.B. is supported by grants from the NIH NIGMS GM063074, National Multiple Sclerosis Society, and the Zachry Foundation (M.A.B). A.M.T. is supported by a NIH NINDS Postdoctoral Fellowship (F32NS092448). Confocal images were acquired at the Spectrography and Bioimaging Facility, National Institute for Basic Biology Core Research Facilities. We thank Dr H. Sano, Dr N. Hatanaka, and Prof. A. Nambu (National Institute for Physiological Sciences, Japan) for technical advice on injections into the motor cortex. We also thank our laboratory members for helpful discussions. The authors declare a conflict of interest that Kazuhiro Ikenaka is the current president of the ISN. All experiments were conducted in compliance with the ARRIVE guidelines.
Publisher Copyright:
© 2018 International Society for Neurochemistry
PY - 2018/11
Y1 - 2018/11
N2 - 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. (Figure presented.).
AB - 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. (Figure presented.).
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U2 - 10.1111/jnc.14553
DO - 10.1111/jnc.14553
M3 - Article
C2 - 30025158
AN - SCOPUS:85052841352
VL - 147
SP - 395
EP - 408
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 3
ER -