The Schizophrenia Susceptibility Gene OPCML Regulates Spine Maturation and Cognitive Behaviors through Eph-Cofilin Signaling

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. : Zhang et al. investigate the mechanism of the schizophrenia-associated opioid-binding protein/cell adhesion molecule (OPCML) in spine maturation and its role in general cognitive function using an Opcml-deficient mouse model. Opcml mediates postsynaptic ephrin-EphB2-cofilin signaling in the regulation of spine maturation, which is involved in the pathogenic mechanism of neurodevelopmental disorders such as schizophrenia. Keywords: schizophrenia, OPCML, spine maturation, cofilin, EphB2 signaling, aripiprazole, cognition