Abstract
Cullin 3 (Cul3) gene, which encodes a core component of the E3 ubiquitin ligase complex that mediates proteasomal degradation, has been identified as a true high-risk factor for autism. Here, by combining behavioral, electrophysiological, and proteomic approaches, we have examined how Cul3 deficiency contributes to the etiology of different aspects of autism. Heterozygous mice with forebrain Cul3 deletion displayed autism-like social interaction impairment and sensory-gating deficiency. Region-specific deletion of Cul3 leads to distinct phenotypes, with social deficits linked to the loss of Cul3 in prefrontal cortex (PFC), and stereotypic behaviors linked to the loss of Cul3 in striatum. Correlated with these behavioral alterations, Cul3 deficiency in forebrain or PFC induces NMDA receptor hypofunction, while Cul3 loss in striatum causes a cell type-specific alteration of neuronal excitability in striatal circuits. Large-scale profiling has identified sets of misregulated proteins resulting from Cul3 deficiency in different regions, including Smyd3, a histone methyltransferase involved in gene transcription. Inhibition or knockdown of Smyd3 in forebrain Cul3-deficient mice ameliorates social deficits and restores NMDAR function in PFC. These results have revealed for the first time a potential molecular mechanism underlying the manifestation of different autism-like behavioral deficits by Cul3 deletion in cortico-striatal circuits.
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Proteomic data will be deposited in a public repository. The access number and the dataset will be available for access.
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Acknowledgements
We thank Xiaoqing Chen for excellent technical support. We acknowledge the support of New York State Center of Excellence in Bioinformatics and Life Sciences and University at Buffalo. This work was supported by: Nancy Lurie Marks Family Foundation (Z.Y.), National Institutes of Health (MH112237 and MH108842) (Z.Y.), Brain and Behavior Foundation (24910) (M.R.) and National Center for Advancing Translational Sciences of the National Institutes of Health (KL2TR001413) (M.R.).
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M.R. performed the behavioral, immunocytochemical, anatomical, and some biochemical experiments, carried out bioinformatic analyses, and wrote the draft. T.T., W.W. and P.Z. performed electrophysiological experiments and analyzed data. X.W. and J.Q. carried out proteomic experiments and analyzed the data. Z.W., L.F., L.Q. and K.M. participated in the biochemical, immunocytochemical, anatomical, and behavioral experiments. Z.Y. designed the experiments, supervised the project, and wrote the paper.
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Rapanelli, M., Tan, T., Wang, W. et al. Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Mol Psychiatry 26, 1491–1504 (2021). https://doi.org/10.1038/s41380-019-0498-x
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DOI: https://doi.org/10.1038/s41380-019-0498-x
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