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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. • Cul3 mutant mice exhibits social behavioral deficits and anxiety-like behaviors • CUL3 deficiency impairs neurotransmission, excitability, and E-I balance • Protein translation and synaptic vesicle turnover are increased in Cul3 mutant mice • Inhibiting protein translation rescues social behavior and neurotransmission deficits Mutations of CUL3 , a component of an E3 ligase complex, are thought of as risk factors for autism spectrum disorders (ASDs) and schizophrenia. Here, Dong et al. show CUL3 deficiency in mice causes social deficits and anxiety-like behaviors and enhances glutamatergic transmission and neuronal excitability. Proteomic analysis reveals eIF4G1, a protein for Cap-dependent translation, as a potential target of CUL3 deficiency. Pharmacological inhibition of eIF4G1 and chemogenetic inhibition of neuronal activity attenuates ASD-associated cellular and behavioral deficits. [ABSTRACT FROM AUTHOR]