Validation of PSD-Zip70 knockout mice as a novel mouse model for neurodevelopmental disorder.

• Project/Area Number: 15K21319
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurophysiology / General neuroscience; Basic / Social brain science
• Research Institution: Iwate Medical University
• Principal Investigator: Mayanagi Taira 岩手医科大学, 医学部, 講師 (20432544)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: PSD-Zip70 / 前頭前皮質 / シナプス / 発達障害 / 行動解析 / ノックアウトマウス / 動物モデル / prefrontal cortex / 不安 / Rap2 / ストレス / 脳機能 / トランスジェニックマウス

Outline of Final Research Achievements

Postsynaptic protein PSD-Zip70 knockout (PSD-Zip70KO) mice possess defects in glutamate synapse transmission in the prefrontal cortex (PFC). To evaluate whether PSD-Zip70KO mice can be used as a modele for neurodevelopmental disorders such as autism spectrum disorder (ASD), we investigated their behavioral traits. As a result, PSD-Zip70KO mice did not exhibit stereotypical behavior or social ability defect, as typical ASD-like behavior. On the other hand, PSD-Zip70KO mice exhibited anxiety even without stress, and the trait was exacerbated by SD stress. Rap2 was activated and phosphorylation level of AMPA receptor GluA2 subunit at Ser880 was prominently elevated in SD-stressed mice, which leads internalization of surface-expressed AMPA receptors and decreases postsynaptic responsiveness. The PSD-Zip70-Rap2-related PFC hypofunction is involved in specifically social stress-induced anxiety. Our finding would provide valuable basis to analyze the mechanism for expression of anxiety.

Research Products

• [Journal Article] Na+/H+ exchange regulatory factor 1 is required for ROMK1 K+ channel expression in the surface membrane of cultured M-1 cortical collecting duct cells. (2017)
  • Author(s): Takashi Suzuki, Kazuyoshi Nakamura, Taira Mayanagi, Kenji Sobue, Manabu Kubokawa.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 489 (2) Issue: 2 Pages: 116-122
  • DOI: 10.1016/j.bbrc.2017.05.104
  • Peer Reviewed
• [Journal Article] Myocardin-related transcription factor A (MRTF-A) activity-dependent cell adhesion is correlated to focal adhesion kinase (FAK) activity. (2016)
  • Author(s): Kishi Takayuki, Mayanagi Taira, Iwabuchi Sadahiro, Akasaka Toshihide, Sobue Kenji.
  • Journal Title: Oncotarget Volume: 7 Issue: 44 Pages: 72113-72130
  • DOI: 10.18632/oncotarget.12350
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Docosahexaenoic Acid Promotes Axon Outgrowth by Translational Regulation of Tau and Collapsin Response Mediator Protein 2 Expression. (2016)
  • Author(s): Toshinari Mita* Taira Mayanagi*, Hiroshi Ichijo, Kentaro Fukumoto, Kotaro Otsuka, Akio Sakai, Kenji Sobue. (* equal contribution)
  • Journal Title: Journal of Biological Chemistry Volume: 291 Issue: 10 Pages: 4955-4965
  • DOI: 10.1074/jbc.m115.693499
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SD-Zip70-deficiency causes prefrontal hypofunction associated with glutamatergic synapse maturation defects by dysregulation of Rap2 activity. (2015)
  • Author(s): Taira Mayanagi, Hiroki Yasuda, and Kenji Sobue
  • Journal Title: Journal of Neuroscience Volume: 35 Issue: 42 Pages: 14327-14340
  • DOI: 10.1523/jneurosci.2349-15.2015
  • Peer Reviewed
• [Presentation] ストレス起因性の不安におけるRap2活性化を伴う前頭前皮質の機能低下の関与 (2018)
  • Author(s): 真柳 平、祖父江 憲治
  • Organizer: 日本生化学会東北支部第84回例会 （矢巾）
• [Presentation] Involvement of Rap2-mediated prefrontal dysfunction in social stress-induced anxiety. (2018)
  • Author(s): Taira Mayanagi, Kenji Sobue
  • Organizer: 第41回日本神経科学大会 （神戸）