Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport
Shogo Yoshihara,
Xuguang Jiang,
Momo Morikawa,
Tadayuki Ogawa,
Sotaro Ichinose,
Hirooki Yabe,
Akiyoshi Kakita,
Manabu Toyoshima,
Yasuto Kunii,
Takeo Yoshikawa,
Yosuke Tanaka,
Nobutaka Hirokawa
Affiliations
Shogo Yoshihara
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan
Xuguang Jiang
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan
Momo Morikawa
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan; Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351-0198, Japan
Tadayuki Ogawa
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan
Sotaro Ichinose
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan
Hirooki Yabe
Departments of Neuropsychiatry and Psychiatry, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
Akiyoshi Kakita
Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
Manabu Toyoshima
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351-0198, Japan
Yasuto Kunii
Departments of Neuropsychiatry and Psychiatry, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
Takeo Yoshikawa
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351-0198, Japan
Yosuke Tanaka
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan
Nobutaka Hirokawa
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan; Corresponding author
Summary: In schizophrenia (SCZ), neurons in the brain tend to undergo gross morphological changes, but the related molecular mechanism remains largely elusive. Using Kif3b+/− mice as a model with SCZ-like behaviors, we found that a high-betaine diet can significantly alleviate schizophrenic traits related to neuronal morphogenesis and behaviors. According to a deficiency in the transport of collapsin response mediator protein 2 (CRMP2) by the KIF3 motor, we identified a significant reduction in lamellipodial dynamics in developing Kif3b+/− neurons as a cause of neurite hyperbranching. Betaine administration significantly decreases CRMP2 carbonylation, which enhances the F-actin bundling needed for proper lamellipodial dynamics and microtubule exclusion and may thus functionally compensate for KIF3 deficiency. Because the KIF3 expression levels tend to be downregulated in the human prefrontal cortex of the postmortem brains of SCZ patients, this mechanism may partly participate in human SCZ pathogenesis, which we hypothesize could be alleviated by betaine administration.
