CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation.

Zhaoqi Dong, Wenbing Chen, Chao Chen, Hongsheng Wang, Wanpeng Cui, Zhibing Tan, Heath Robinson, Nannan Gao, Bin Luo, Lei Zhang, Kai Zhao, Wen-Cheng Xiong, Lin Mei

Neuron 2020 Feb 05

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Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with symptoms including social deficits, anxiety, and communication difficulties. However, ASD pathogenic mechanisms are poorly understood. Mutations of CUL3, which encodes Cullin 3 (CUL3), a component of an E3 ligase complex, are thought of as risk factors for ASD and schizophrenia (SCZ). CUL3 is abundant in the brain, yet little is known of its function. Here, we show that CUL3 is critical for neurodevelopment. CUL3-deficient mice exhibited social deficits and anxiety-like behaviors with enhanced glutamatergic transmission and neuronal excitability. Proteomic analysis revealed eIF4G1, a protein for Cap-dependent translation, as a potential target of CUL3. ASD-associated cellular and behavioral deficits could be rescued by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity. Thus, CUL3 is critical to neural development, neurotransmission, and excitation-inhibition (E-I) balance. Our study provides novel insight into the pathophysiological mechanisms of ASD and SCZ. Copyright © 2019 Elsevier Inc. All rights reserved.

Citation

Zhaoqi Dong, Wenbing Chen, Chao Chen, Hongsheng Wang, Wanpeng Cui, Zhibing Tan, Heath Robinson, Nannan Gao, Bin Luo, Lei Zhang, Kai Zhao, Wen-Cheng Xiong, Lin Mei. CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation. Neuron. 2020 Feb 05;105(3):475-490.e6