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

ABSTRACT: 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.

SUBMITTER: Dong Z

PROVIDER: S-EPMC7007399 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Dong Zhaoqi Z Chen Wenbing W Chen Chao C Wang Hongsheng H Cui Wanpeng W Tan Zhibing Z Robinson Heath H Gao Nannan N Luo Bin B Zhang Lei L Zhao Kai K Xiong Wen-Cheng WC Mei Lin L

Neuron 20191125 3

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-de ...[more]

PMID: 31780330

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Project description:BackgroundCurrent clinical balance assessment tools do not aim to help therapists identify the underlying postural control systems responsible for poor functional balance. By identifying the disordered systems underlying balance control, therapists can direct specific types of intervention for different types of balance problems.ObjectiveThe goal of this study was to develop a clinical balance assessment tool that aims to target 6 different balance control systems so that specific rehabilitation approaches can be designed for different balance deficits. This article presents the theoretical framework, interrater reliability, and preliminary concurrent validity for this new instrument, the Balance Evaluation Systems Test (BESTest).DesignThe BESTest consists of 36 items, grouped into 6 systems: "Biomechanical Constraints," "Stability Limits/Verticality," "Anticipatory Postural Adjustments," "Postural Responses," "Sensory Orientation," and "Stability in Gait."MethodsIn 2 interrater trials, 22 subjects with and without balance disorders, ranging in age from 50 to 88 years, were rated concurrently on the BESTest by 19 therapists, students, and balance researchers. Concurrent validity was measured by correlation between the BESTest and balance confidence, as assessed with the Activities-specific Balance Confidence (ABC) Scale.ResultsConsistent with our theoretical framework, subjects with different diagnoses scored poorly on different sections of the BESTest. The intraclass correlation coefficient (ICC) for interrater reliability for the test as a whole was .91, with the 6 section ICCs ranging from .79 to .96. The Kendall coefficient of concordance among raters ranged from .46 to 1.00 for the 36 individual items. Concurrent validity of the correlation between the BESTest and the ABC Scale was r=.636, P<.01.LimitationsFurther testing is needed to determine whether: (1) the sections of the BESTest actually detect independent balance deficits, (2) other systems important for balance control should be added, and (3) a shorter version of the test is possible by eliminating redundant or insensitive items.ConclusionsThe BESTest is easy to learn to administer, with excellent reliability and very good validity. It is unique in allowing clinicians to determine the type of balance problems to direct specific treatments for their patients. By organizing clinical balance test items already in use, combined with new items not currently available, the BESTest is the most comprehensive clinical balance tool available and warrants further development.

Dataset Information

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

Publications

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

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