Cell Reports
Volume 29, Issue 1, 1 October 2019, Pages 49-61.e7
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Article
The Schizophrenia Susceptibility Gene OPCML Regulates Spine Maturation and Cognitive Behaviors through Eph-Cofilin Signaling

https://doi.org/10.1016/j.celrep.2019.08.091Get rights and content
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Highlights

  • Schizophrenia-related OPCML abounds in the dendritic spine and regulates F-actin dynamics

  • Opcml stabilizes spine morphology through the ephrin-EphB2-cofilin signaling pathway

  • Opcml-deficient mice exhibit impaired sensory gating and cognitive deficits

  • Abnormal phenotypes in Opcml−/− mice can be ameliorated by aripiprazole treatment

Summary

Previous genetic and biological evidence converge on the involvement of synaptic dysfunction in schizophrenia, and OPCML, encoding a synaptic membrane protein, is reported to be genetically associated with schizophrenia. However, its role in the pathophysiology of schizophrenia remains largely unknown. Here, we found that Opcml is strongly expressed in the mouse hippocampus; ablation of Opcml leads to reduced phosphorylated cofilin and dysregulated F-actin dynamics, which disturbs the spine maturation. Furthermore, Opcml interacts with EphB2 to control the stability of spines by regulating the ephrin-EphB2-cofilin signaling pathway. Opcml-deficient mice display impaired cognitive behaviors and abnormal sensorimotor gating, which are similar to features in neuropsychiatric disorders such as schizophrenia. Notably, the administration of aripiprazole partially restores the abnormal behaviors in Opcml−/− mice by increasing the phosphorylated cofilin level and facilitating spine maturation. We demonstrated a critical role of the schizophrenia-susceptible gene OPCML in spine maturation and cognitive behaviors via regulating the ephrin-EphB2-cofilin signaling pathway, providing further insights into the characteristics of schizophrenia.

Keywords

schizophrenia
OPCML
spine maturation
cofilin
EphB2 signaling
aripiprazole
cognition

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