CUL3 deficiency causes social deficits and anxiety-like behaviors by impairing excitation-inhibition balance via promoting Cap-dependent translation
Zhaoqi Dong*,1, Wenbing Chen*,2, Chao Chen3, Hongsheng Wang1, Wanpeng Cui1, Zhibing Tan1, Heath Robinson1, Nannan Gao1, Bin Luo2, Lei Zhang1, Kai Zhao1, Wen-Cheng Xiong1,4 and Lin Mei1,4,5
1Department of Neurosciences, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH
2Institute of Life Science, Nanchang University, Nanchang, China.
3The Laboratory of Vector Biology and Control, College of Engineering, Beijing Normal University, Zhuhai, China.
4Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH
*These authors contributed equally.
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 showed 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 reveals novel insight into pathophysiological mechanisms of ASD and SCZ.