CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Abnormality in gene transcription or protein translation may underlie the involvement of Cul3 in neurodevelopmental disorders.
“Abnormality in gene transcription or protein translation may underlie the involvement of Cul3 in neurodevelopmental disorders [87, 88].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [88]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577 · see citing works
Baio, J., Wiggins, L., Christensen, D. L., Maenner, M. J., Daniels, J., Warren, Z., Kurzius-Spencer, M., Zahorodny, W., Robinson, C., Rosenberg, et al. (2018) · MMWR. Surveillance Summaries · doi:10.15585/mmwr.ss6706a1 · Cited by 6,078 · see citing works
Synaptic, transcriptional and chromatin genes disrupted in autism
Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., et al. (2014) · Nature · doi:10.1038/nature13772 · Cited by 2,746 · see citing works
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., et al. (2012) · Nature · doi:10.1038/nature10989 · Cited by 2,165 · see citing works
Moy, S. S., Nadler, J. J., Perez, A., Barbaro, R. P., Johns, J. M., Magnuson, T. R., Piven, J., & Crawley, J. N. (2004) · Genes, Brain and Behavior · doi:10.1111/j.1601-1848.2004.00076.x · Cited by 1,545 · see citing works
Erroneous analyses of interactions in neuroscience: A problem of significance
Nieuwenhuis, S., Forstmann, B. U., & Wagenmakers, E.-J. (2011) · Nature Neuroscience · doi:10.1038/nn.2886 · Cited by 864 · see citing works
FMR1 and the fragile X syndrome: Human genome epidemiology review
Crawford, D. C., Acuña, J. M., & Sherman, S. L. (2001) · Genetics in Medicine · doi:10.1097/00125817-200109000-00006 · Cited by 711 · see citing works
Bourgeron, T. (2009) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2009.06.003 · Cited by 637 · see citing works
Autism-related deficits via dysregulated eIF4E-dependent translational control
Gkogkas, C. G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., Vasuta, C., Yee, S., Truitt, M., Dallaire, P., et al. (2013) · Nature · doi:10.1038/nature11628 · Cited by 522 · see citing works
Hippocampus in autism: a Golgi analysis
Raymond, G. V., Bauman, M. L., & Kemper, T. L. (1995) · Acta Neuropathologica · doi:10.1007/s004010050401 · Cited by 387 · see citing works
Prader–Willi syndrome and Angelman syndrome
Buiting, K. (2010) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.30273 · Cited by 336 · see citing works
Amygdalar and hippocampal substrates of anxious temperament differ in their heritability
Oler, J. A., Fox, A. S., Shelton, S. E., Rogers, J., Dyer, T. D., Davidson, R. J., Shelledy, W., Oakes, T. R., Blangero, J., & Kalin, N. H. (2010) · Nature · doi:10.1038/nature09282 · Cited by 208 · see citing works
Plasma amino acid levels in children with autism and their families
Aldred, S., Moore, K. M., Fitzgerald, M., & Waring, R. H. (2003) · Journal of Autism and Developmental Disorders · doi:10.1023/a:1022238706604 · Cited by 188 · see citing works
Solving the Autism Puzzle a Few Pieces at a Time
Schaaf, C. P., & Zoghbi, H. Y. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.025 · Cited by 166 · see citing works
Cerebral blood flow in immediate and sustained anxiety
Hasler, G., Fromm, S., Alvarez, R. P., Luckenbaugh, D. A., Drevets, W. C., & Grillon, C. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.5369-06.2007 · Cited by 163 · see citing works
Lrp4 in astrocytes modulates glutamatergic transmission
Sun, X.-D., Li, L., Liu, F., Huang, Z.-H., Bean, J. C., Jiao, H.-F., Barik, A., Kim, S.-M., Wu, H., Shen, C., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4326 · Cited by 102 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
16p11.2 Copy Number Variations and Neurodevelopmental Disorders
Rein, B., & Yan, Z. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.09.001 · Cited by 160 · see citing works
Liu, Y., Ouyang, P., Zheng, Y., Mi, L., Zhao, J., Ning, Y., & Guo, W. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.664535 · Cited by 129 · see citing works
- Authors
- Dong, Z., Chen, W., Chen, C., Wang, H., Cui, W., Tan, Z., Robinson, H., Gao, N., Luo, B., Zhang, L., Zhao, K., Xiong, W.-C., & Mei, L.
- Affiliations
- Case Western Reserve University (US)
- Beijing Normal University (CN)
- Louis Stokes Cleveland VA Medical Center (US)
- Corresponding author
- Mei, Lin
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 105
- Issue
- 3
- Pages
- 475-490.e6
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC7007399
- OpenAlex
- W2990950320
- Cited by
- 109
- References
- 16
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 15 · 2023: 19 · 2022: 15 · 2021: 18 · 2020: 14
- FWCI
- 7.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CUL3, autism spectrum disorder, schizophrenia, social dysfunction, anxiety-like behavior, excitation-inhibition balance, glutamatergic neurotransmission, neuronal excitability, cap-dependent translation, eIF4G1, E3 ubiquitin ligase, brain development, mouse model
- MeSH terms
- Autism Spectrum Disorder, Animals, Anxiety, Brain, Cells, Cultured, Humans, Locomotion, Male, Mice, Inbred C57BL, Mice, Transgenic, Protein Biosynthesis, Excitatory Postsynaptic Potentials, Cullin Proteins, Mice, Inhibitory Postsynaptic Potentials, HEK293 Cells, Social Skills
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
