Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia

Akira Sobue, Itaru Kushima, Taku Nagai, Wei Shan, Takao Kohno, Branko Aleksic, Yuki Aoyama, Daisuke Mori, Yuko Arioka, Naoko Kawano, Maeri Yamamoto, Mitsuharu Hattori, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki

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Abstract

Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

Original languageEnglish
Article number13046
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 01-12-2018

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Genetic Models
Schizophrenia
Animal Models
Learning
Methamphetamine
Social Behavior
Extracellular Matrix Proteins
Brain
reelin protein
Antipsychotic Agents
Psychiatry
Exons
Dopamine
Spine
Anxiety
Mutation
Serum

All Science Journal Classification (ASJC) codes

  • General

Cite this

Sobue, A., Kushima, I., Nagai, T., Shan, W., Kohno, T., Aleksic, B., ... Ozaki, N. (2018). Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia. Scientific reports, 8(1), [13046]. https://doi.org/10.1038/s41598-018-31390-w
Sobue, Akira ; Kushima, Itaru ; Nagai, Taku ; Shan, Wei ; Kohno, Takao ; Aleksic, Branko ; Aoyama, Yuki ; Mori, Daisuke ; Arioka, Yuko ; Kawano, Naoko ; Yamamoto, Maeri ; Hattori, Mitsuharu ; Nabeshima, Toshitaka ; Yamada, Kiyofumi ; Ozaki, Norio. / Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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abstract = "Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.",
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Sobue, A, Kushima, I, Nagai, T, Shan, W, Kohno, T, Aleksic, B, Aoyama, Y, Mori, D, Arioka, Y, Kawano, N, Yamamoto, M, Hattori, M, Nabeshima, T, Yamada, K & Ozaki, N 2018, 'Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia', Scientific reports, vol. 8, no. 1, 13046. https://doi.org/10.1038/s41598-018-31390-w

Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia. / Sobue, Akira; Kushima, Itaru; Nagai, Taku; Shan, Wei; Kohno, Takao; Aleksic, Branko; Aoyama, Yuki; Mori, Daisuke; Arioka, Yuko; Kawano, Naoko; Yamamoto, Maeri; Hattori, Mitsuharu; Nabeshima, Toshitaka; Yamada, Kiyofumi; Ozaki, Norio.

In: Scientific reports, Vol. 8, No. 1, 13046, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia

AU - Sobue, Akira

AU - Kushima, Itaru

AU - Nagai, Taku

AU - Shan, Wei

AU - Kohno, Takao

AU - Aleksic, Branko

AU - Aoyama, Yuki

AU - Mori, Daisuke

AU - Arioka, Yuko

AU - Kawano, Naoko

AU - Yamamoto, Maeri

AU - Hattori, Mitsuharu

AU - Nabeshima, Toshitaka

AU - Yamada, Kiyofumi

AU - Ozaki, Norio

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

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