@article{970d1e687e594cb99385bb0e2aa10b64,
title = "Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders",
abstract = "Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.",
author = "Takanobu Nakazawa and Ryota Hashimoto and Kazuto Sakoori and Yuki Sugaya and Asami Tanimura and Yuki Hashimotodani and Kazutaka Ohi and Hidenaga Yamamori and Yuka Yasuda and Satomi Umeda-Yano and Yuji Kiyama and Kohtarou Konno and Takeshi Inoue and Kazumasa Yokoyama and Takafumi Inoue and Shusuke Numata and Tohru Ohnuma and Nakao Iwata and Norio Ozaki and Hitoshi Hashimoto and Masahiko Watanabe and Toshiya Manabe and Tadashi Yamamoto and Masatoshi Takeda and Masanobu Kano",
note = "Funding Information: We thank S. Kawata for help with the data analysis, A. Ito for discussions, and Machika Watanabe, K. Matsuyama and M. Sekiguchi for technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research (21680033 to T.N., 22390225 and 23659565 to R.H., 25000015 to M.K.) from the Japan Society for the Promotion of Science (JSPS), a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports, Culture and Technology in Japan (MEXT), the Strategic Research Program for Brain Sciences (project D) from MEXT, Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from MEXT, the Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2603; H.H.) from MEXT, research grants from the Ministry of Health, Labour and Welfare in Japan (H22-seishin-ippan-001), the Health and Labour Sciences Research Grants for Comprehensive Research on Persons with Disabilities and Brain/MINDS from the Japan Agency for Medical Research and Development (AMED), and a research grant from Takeda Science Foundation (to T.N.).",
year = "2016",
month = feb,
day = "3",
doi = "10.1038/ncomms10594",
language = "English",
volume = "7",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Research",
}