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Nat Commun. 2016 Feb 3;7:10594. doi: 10.1038/ncomms10594.

Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders.

Author information

1
Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
2
Division of Oncology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
3
iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita 565-0871, Japan.
4
Department of Psychiatry, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
5
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita 565-0871, Japan.
6
Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
7
Division of Neuronal Network, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
8
Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
9
Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo 162-8480, Japan.
10
Department of Psychiatry, Course of Integrated Brain Sciences, School of Medicine, University of Tokushima, Tokushima 770-8503, Japan.
11
Department of Psychiatry, Juntendo University School of Medicine, Tokyo 113-0033, Japan.
12
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake 470-1192, Japan.
13
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan.
14
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita 565-0871, Japan.
15
Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son 904-0495, Japan.

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.

PMID:
26839058
PMCID:
PMC4742909
DOI:
10.1038/ncomms10594
[Indexed for MEDLINE]
Free PMC Article

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