Implications for the development of new treatment strategies for neuropsychiatric disorders.
A collaborative research team from Osaka University and The University of Tokyo has identified a critical role for intracellular protein trafficking in supporting higher brain functions such as learning and memory. Their work demonstrates that the molecule ARHGAP33 regulates synaptic function and related behaviors by controlling the intracellular movement of key receptor proteins. Loss of ARHGAP33 in experimental models produces synaptic deficits and behavioral changes that resemble aspects of human neuropsychiatric disorders.
Led by Takanobu Nakazawa (Specially Appointed Associate Professor, Osaka University), Masanobu Kano (Professor, The University of Tokyo) and Ryota Hashimoto (Associate Professor, Osaka University), the investigators created ARHGAP33 knockout (KO) mice to probe the molecular and cellular roles of ARHGAP33 in the brain. Detailed cellular analyses revealed impaired dendritic spine development in neurons from ARHGAP33 KO mice, together with reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). These synaptic abnormalities were accompanied by measurable behavioral deficits: the ARHGAP33 KO mice displayed impairments in working memory and reduced prepulse inhibition, phenotypes that are relevant to conditions such as schizophrenia and other neuropsychiatric disorders.
To uncover the mechanism linking ARHGAP33 loss to synaptic and behavioral dysfunction, the team examined intracellular trafficking pathways. They found that ARHGAP33 is concentrated at the Golgi apparatus and plays a central role in moving the Tropomyosin receptor kinase B (TrkB) receptor—a principal neurotrophin receptor for brain-derived neurotrophic factor (BDNF)—to synaptic sites. Proper delivery of TrkB to synapses is essential for synapse formation, maintenance and plasticity. In the absence of ARHGAP33, TrkB fails to reach synaptic locations efficiently, producing reduced synaptic TrkB expression and downstream synaptic deficits that help explain the observed cognitive and sensorimotor gating impairments.
Mechanistic studies further revealed that ARHGAP33 cooperates with the sorting receptor SORT1 to regulate TrkB trafficking. Consistent with this pathway’s importance for brain function, the investigators report that pharmacological enhancement of TrkB signaling can rescue the synaptic and behavioral defects in ARHGAP33 KO mice, supporting the view that impaired TrkB trafficking is a causal contributor to the phenotype. The research group also identified associations between human ARHGAP33 and brain phenotypes, and noted reduced SORT1 expression in samples from people with schizophrenia, linking the animal findings to human neuropsychiatric disease biology.
These discoveries position ARHGAP33-dependent intracellular trafficking as a previously underappreciated molecular mechanism essential for synapse development and higher-order brain functions. By tying defects in protein sorting and transport to measurable synaptic and behavioral outcomes, the study highlights intracellular trafficking pathways as potential points of intervention. Restoring TrkB signaling at synapses, enhancing trafficking efficiency, or targeting cooperating molecules such as SORT1 are conceivable therapeutic strategies that merit further preclinical and translational exploration.
The molecular pathophysiology underlying many neuropsychiatric disorders remains incompletely understood, and current treatments are often limited. This work provides new insight into how disruptions of intracellular protein trafficking can lead to synaptic dysfunction and behavioral abnormalities linked to psychiatric illness. Because the synaptic deficits in ARHGAP33-deficient mice were reversible by pharmacological means that enhance TrkB signaling, the findings offer a promising rationale for developing treatments that specifically address trafficking-dependent synaptic dysfunction in conditions like schizophrenia.
Funding: This research was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and by Grant-in-Aid for Scientific Research on Innovative Areas.
Source: Saori Obayashi – Osaka University
Image Source: The image is credited to Takanobu Nakazawa (Osaka University) et al.
Original Research: “Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders,” Nature Communications. Published online February 3, 2016. doi:10.1038/ncomms10594
Abstract
Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders
Intracellular trafficking of receptor proteins is essential for neurons to respond to extracellular signals during neural circuit formation and refinement. The precise mechanisms that deliver neurotrophin receptors to synapses have been unclear. This study demonstrates that ARHGAP33, a brain-enriched sorting protein, functions as a regulator of TrkB trafficking. ARHGAP33 knockout mice show decreased synaptic TrkB, impaired dendritic spine development and behavioral abnormalities related to neuropsychiatric disorders. Those deficits can be rescued by pharmacological enhancement of TrkB signaling. Mechanistically, ARHGAP33 interacts with SORT1 to coordinate TrkB transport. Human genetic and expression data link ARHGAP33 and SORT1 to brain phenotypes and to schizophrenia, suggesting that disruption of ARHGAP33/SORT1-mediated TrkB trafficking may represent a novel molecular pathology underlying certain neuropsychiatric conditions.