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

All Science Journal Classification (ASJC) codes

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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, 8(1), [13046]. https://doi.org/10.1038/s41598-018-31390-w