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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]

Heat perception enables acute avoidance responses to prevent tissue damage and maintain body thermal homeostasis. Unlike other modalities, how heat signals are processed in the spinal cord remains unclear. By single-cell gene profiling, we identified ErbB4, a transmembrane tyrosine kinase, as a novel marker of heat-sensitive spinal neurons in mice. Ablating spinal ErbB4+ neurons attenuates heat sensation. These neurons receive monosynaptic inputs from TRPV1+ nociceptors and form excitatory synapses onto target neurons. Activation of ErbB4+ neurons enhances the heat response, while inhibition reduces the heat response. We showed that heat sensation is regulated by NRG1, an activator of ErbB4, and it involves dynamic activity of the tyrosine kinase that promotes glutamatergic transmission. Evidence indicates that the NRG1-ErbB4 signaling is also engaged in hypersensitivity of pathological pain. Together, these results identify a spinal neuron connection consisting of ErbB4+ neurons for heat sensation and reveal a regulatory mechanism by the NRG1-ErbB4 signaling. [Display omitted] • Spinal ErbB4+ neurons are activated by heat and synapsed by TRPV1+ nociceptors • Heat sensation is reduced by ErbB4+ neuron ablation or inhibition • Augmented effect on heat sensation by inhibiting ErbB4+, SST+, and CCK+ neurons together • NRG1-ErbB4 signaling promotes heat sensation and hypersensitivity How heat signals are processed in the spinal cord remains unclear. Wang et al. found that ErbB4+ excitatory interneurons are activated by noxious heat, and they participate in heat sensation in mice. In addition, the neuregulin-ErbB4 signaling regulates heat sensation and contributes to heat hypersensitivity under pathological conditions. [ABSTRACT FROM AUTHOR]