Disruption of Ninjurin1 Leads to Repetitive and Anxiety-Like Behaviors in Mice

Hoang Le, Bum Ju Ahn, Hye Shin Lee, Anna Shin, Sujin Chae, Sung Yi Lee, Min Wook Shin, Eun Ji Lee, Jong Ho Cha, Taekwon Son, Ji Hae Seo, Hee Jun Wee, Hyo Jong Lee, Yongwoo Jang, Eng H. Lo, Sejin Jeon, Goo Taeg Oh, Daesoo Kim, Kyu Won Kim

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Over the last few decades, molecular neurobiology has uncovered many genes whose deficiency in mice results in behavioral traits associated with human neuropsychiatric disorders such as autism, obsessive-compulsive disorder (OCD), and schizophrenia. However, the etiology of these common diseases remains enigmatic with the potential involvement of a battery of genes. Here, we report abnormal behavioral phenotypes of mice deficient in a cell adhesion molecule Ninjurin 1 (Ninj1), which are relevant to repetitive and anxiety behaviors of neuropsychiatric disorders. Ninj1 knockout (KO) mice exhibit compulsive grooming-induced hair loss and self-made lesions as well as increased anxiety-like behaviors. Histological analysis reveals that Ninj1 is predominantly expressed in cortico-thalamic circuits, and neuron-specific Ninj1 conditional KO mice manifest aberrant phenotypes similar to the global Ninj1 KO mice. Notably, the brains of Ninj1 KO mice display altered synaptic transmission in thalamic neurons as well as a reduced number of functional synapses. Moreover, the disruption of Ninj1 leads to glutamatergic abnormalities, including increased ionotropic glutamate receptors but reduced glutamate levels. Furthermore, chronic treatment with fluoxetine, a drug reportedly ameliorates compulsive behaviors in mice, prevents progression of hair loss and alleviates the compulsive grooming and anxiety-like behavior of Ninj1 KO mice. Collectively, our results suggest that Ninj1 could be involved in neuropsychiatric disorders associated with impairments of repetitive and anxiety behaviors.

Original languageEnglish
Pages (from-to)7353-7368
Number of pages16
JournalMolecular Neurobiology
Volume54
Issue number9
DOIs
StatePublished - 1 Nov 2017

Bibliographical note

Funding Information:
Acknowledgments The authors thank Dr. Ji-Hyeon Park for animal behavior assistance; Dr. Hyun-Ho Kim for confocal microscopy setting; Hoang-Kieu-Chi Ngo for discussions, comments, and reading of the manuscript; Dr. Jeongjin Kim and Minju Jeong (Dept. of Biological Sciences, KAIST, Korea) for the electrophysiological experiments; and Dr. Melinda Chan and KOMP project (UC Davis, USA) for Ninj1tm1a mice. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) through the Global Research Laboratory Program (2011-0021874), Brain Korea 21 Program (2013-036038), the Global Core Research Center (GCRC) Program (2011-0030001), the NRF grant funded by the Korea government (MSIP) (2015R1C1A2A01054446 to H.S. Lee), Basic Science Research Program (2013R1A1A2058956 to J.H. Seo), and the International Cooperation Program (2014K2A1C2074279). E.H. Lo is the recipient of NIH grants (R37-NS37074, R01-76694, and P01-NS55104). G.T.O. was supported by the NRF grant funded by the Korea government (MEST) (No. 2013003407).

Funding Information:
The authors thank Dr. Ji-Hyeon Park for animal behavior assistance; Dr. Hyun-Ho Kim for confocal microscopy setting; Hoang-Kieu-Chi Ngo for discussions, comments, and reading of the manuscript; Dr. Jeongjin Kim and Minju Jeong (Dept. of Biological Sciences, KAIST, Korea) for the electrophysiological experiments; and Dr. Melinda Chan and KOMP project (UC Davis, USA) for Ninj1tm1amice. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) through the Global Research Laboratory Program (2011-0021874), Brain Korea 21 Program (2013-036038), the Global Core Research Center (GCRC) Program (2011-0030001), the NRF grant funded by the Korea government (MSIP) (2015R1C1A2A01054446 to H.S. Lee), Basic Science Research Program (2013R1A1A2058956 to J.H. Seo), and the International Cooperation Program (2014K2A1C2074279). E.H. Lo is the recipient of NIH grants (R37-NS37074, R01-76694, and P01-NS55104). G.T.O. was supported by the NRF grant funded by the Korea government (MEST) (No. 2013003407). H.L. performed biological, behavioral experiments, constructed Ninj1 conditional knockout mice, analyzed data, prepared the figure, and wrote the manuscript. B.J.A. constructed Ninj1 knockout mice system and Ninj1 antibody, analyzed data, prepared the figure, and edited the manuscript. H.S.L. coordinated collaborations, analyzed data, and prepared the figure and manuscript. S.Y.L. performed behavioral tests, electron microscopy. M.W.S. helped with biological experiments and edited the manuscript. E.-J.L. prepared Ninj1 antibody. J.-H.C. helped with immunostaining, animal experiments, and data discussion. J.H.S., H.-J.W., T.S., and E.H.L. helped with discussion of hypothesis. Y.W.J. gave antibodies of synaptic proteins and helped with data discussion. H.-J.L. initiated Ninj1 study and helped with data discussion. S.J.J. and G.T.O. provided Ninj1 knockout mice. A.N.S., S.J.C., and D.S.K. conducted electrophysiological experiments. H.L. and K.-W.K. developed the hypothesis. K.-W.K. supervised this project, analyzed data, and wrote the manuscript. All authors read and approved the manuscript. The authors declare that they have no conflict of interest.

Publisher Copyright:
© 2016, Springer Science+Business Media New York.

Keywords

  • Anxiety-like behavior
  • Fluoxetine
  • Glutamate receptors
  • Ninj1
  • OCD
  • Repetitive behavior

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