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

Kazuo Kunisawa, Takeshi Shimizu, Itaru Kushima, Branko Aleksic, Daisuke Mori, Yasuyuki Osanai, Kenta Kobayashi, Anna M. Taylor, Manzoor A. Bhat, Akiko Hayashi, Hiroko Baba, Norio Ozaki, Kazuhiro Ikenaka

Research output: Contribution to journalArticle

Abstract

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.).

Original languageEnglish
Pages (from-to)395-408
Number of pages14
JournalJournal of Neurochemistry
Volume147
Issue number3
DOIs
Publication statusPublished - 01-11-2018

Fingerprint

Aquaporin 3
Schizophrenia
Knockout Mice
galactosylceramide sulfotransferase
Contactins
Ranvier's Nodes
Dependovirus
Oligodendroglia
Motor Cortex
Ablation
Viruses
Gene expression
Neuroglia
Neurons
Axons
Retina
Genes
RNA
Apoptosis
Membranes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

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. / Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability. In: Journal of Neurochemistry. 2018 ; Vol. 147, No. 3. pp. 395-408.
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abstract = "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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Kunisawa, K, Shimizu, T, Kushima, I, Aleksic, B, Mori, D, Osanai, Y, Kobayashi, K, Taylor, AM, Bhat, MA, Hayashi, A, Baba, H, Ozaki, N & Ikenaka, K 2018, 'Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability', Journal of Neurochemistry, vol. 147, no. 3, pp. 395-408. https://doi.org/10.1111/jnc.14553

Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability. / 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.

In: Journal of Neurochemistry, Vol. 147, No. 3, 01.11.2018, p. 395-408.

Research output: Contribution to journalArticle

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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

PY - 2018/11/1

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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.).

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