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Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling

Molecular Psychiatry volume 27, pages 2414–2424 (2022)Cite this article

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Abstract

The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation, and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux, and conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.

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Fig. 1: Aberrant locomotor, social, affective, and cognitive behaviors in CYLD KO mice.
Fig. 2: Enhanced postsynaptic efficacy in CYLD KO mice.
Fig. 3: Augmented short-term but impaired long-term synaptic plasticity in CYLD KO mice.
Fig. 4: CYLD promotes synapse pruning.
Fig. 5: Impaired autophagy and heightened Akt-mTOR signaling in CYLD KO hippocampus.
Fig. 6: CYLD drives spine elimination via Akt and autophagy.
Fig. 7: Rapamycin rescues spine density, synaptic efficacy, and LTD in CYLD KO mice.

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Acknowledgements

We thank members of the laboratory for critiques and comments. This work was supported by NIH Grants MH106489, NS093097, NS122351, RR026761 (to W.-D.Y.) and RR000168 (to the New England Primate Research Center/Harvard Medical School).

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA

    Alexis S. Zajicek, Hongyu Ruan, Huihui Dai, Mary C. Skolfield, Hannah L. Phillips, Wendi J. Burnette & Wei-Dong Yao

  2. Neuroscience Graduate Program, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA

    Alexis S. Zajicek, Mary C. Skolfield, Hannah L. Phillips, Wendi J. Burnette & Wei-Dong Yao

  3. Friedman Brain Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Behnam Javidfar & Schahram Akbarian

  4. Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Shao-Cong Sun

  5. Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA

    Wei-Dong Yao

  6. Harvard Medical School, New England Primate Research Center, Southborough, MA, USA

    Wei-Dong Yao

  7. Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Wei-Dong Yao

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  1. Alexis S. Zajicek
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Contributions

A.S.Z., H.R. and W.-D.Y. designed research; A.S.Z., H.R., H.D., M.C.M., H.L.P., W.J.B. and B.J. performed research; S.C.S. contributed reagents; A.S.Z, H.R., H.D., M.C.S., H.L.P., W.J.B., B.J., S.A. and W.-D.Y. analyzed data; and A.S.Z., H.R. and W.-D.Y. wrote the paper.

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Correspondence to Wei-Dong Yao.

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Zajicek, A.S., Ruan, H., Dai, H. et al. Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling. Mol Psychiatry 27, 2414–2424 (2022). https://doi.org/10.1038/s41380-022-01571-1

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