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Loss of Necdin causes social deficit and aberrant synaptic function through destabilization of SynGAP

Molecular Psychiatry (2025)Cite this article

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Abstract

The Ras GTPase-activating protein SynGAP interacts with PSD95 to regulate synaptic morphology and function at the postsynaptic density in neurons. Haploinsufficiency of SYNGAP1 has been linked to autism spectrum disorders (ASD) and intellectual disability (ID). While transcriptional and translational regulation of SYNGAP1 has been extensively explored, the mechanisms governing its protein homeostasis remain largely elusive. In this study, we discovered that Necdin, a protein linked to Prader-Willi syndrome (PWS), interacts with SynGAP and regulates its stability through the SGT1-HSP90 chaperone machinery; notably, depletion of Necdin results in decreased SynGAP protein levels in mice. Loss of Necdin lead to impaired sociability, accompanied by an increased number of dendritic spines and a higher proportion of mature spines in pyramidal neurons of the medial prefrontal cortex (mPFC) in mice. Electrophysiological recordings revealed elevated frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) and reduced amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in these neurons. Targeted viral overexpression of Syngap1 in the mPFC of Necdin-deficient mice rescued the deficits in sociability, synaptic function, and dendritic spine morphology. Collectively, our findings reveal Necdin as a key regulator of SynGAP protein homeostasis and highlight the contribution of post-translational regulation in the pathogenesis of ASD.

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Fig. 1: Social deficit in mice lacking Necdin.
Fig. 2: Loss of Necdin led to increased excitatory synaptic transmission.
Fig. 3: Increased expression of immediate early response genes (IEGs) and c-Fos in the mPFC of Ndn−p/+m mice.
Fig. 4: Necdin interacted with stabilized SynGAP protein.
Fig. 5: Necdin stabilized SynGAP through SGT1-HSP90 chaperone machinery.
Fig. 6: Overexpression of Syngap1 in the mPFC rescued the aberrant synaptic function and social deficit in Ndn−p/+m mice.
Fig. 7: Schematic diagram of the working model.

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Data availability

The IP-MS datasets generated in this study have been deposited in two public repositories: the ProteomeXchange Consortium (PXD064040) and the iProX database (IPX0011995000). All other raw data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This project is funded by the National Natural Science Foundation of China (32371218, 31972913, 82070815, 32400690); Hunan Provincial grants (2021DK2001, 2023SK2084, 2023RC4001, 2024JJ5540, 2025DK2004, 2025JJ30041, 2025JJ60134); Guangdong Key Project in “Development of new tools for diagnosis and treatment of Autism” (2018B030335001).

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  1. These authors contributed equally: Xiangyu Li, Ibrahim Bader.

Authors and Affiliations

  1. Furong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, P. R. China

    Xiangyu Li, Ibrahim Bader, Xin Li, Renbin Lu, Dengfeng Liu, Suixin Deng & Jia-Da Li

  2. Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, 410078, Hunan, P. R. China

    Xiangyu Li, Ibrahim Bader, Xin Li, Dengfeng Liu, Suixin Deng & Jia-Da Li

  3. Hunan Key Laboratory of Medical Genetics, Changsha, 410078, Hunan, P. R. China

    Xiangyu Li, Xin Li, Dengfeng Liu, Suixin Deng & Jia-Da Li

  4. Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Diseases, Changsha, 410078, Hunan, P. R. China

    Xiangyu Li, Xin Li, Dengfeng Liu, Suixin Deng & Jia-Da Li

  5. MOE Key Laboratory of Rare Pediatric Diseases, Changsha, 410078, Hunan, P. R. China

    Xiangyu Li, Xin Li, Dengfeng Liu, Suixin Deng, Huadie Liu & Jia-Da Li

  6. Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Zhiheng Chen

  7. Department of Neurosurgery, Jinshan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Fudan University, Shanghai, 200032, China

    Yousheng Shu

  8. Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, P. R. China

    Huadie Liu

  9. Department of Laboratory Animals, Central South University, Changsha, Hunan, China

    Jing Zhang

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Contributions

J.Z., H.L. and J-D.L. conceived the experiments. X.L. performed the behavioral experiments, spine morphology and SynGAP rescuing experiments. X.L. and I.B. performed the electrophysiology analysis under the supervision of Y.S. and S.D.. X.L., R.L. and D.L. performed the RNA-seq and IP-MS analysis under the supervision of Z.C.. J.Z. performed the Necdin-SynGAP interaction and influence of Necdin-SGT1-HSP90 on the stability of SynGAP. J-D.L., J.Z. and H.L. supervised the project. X.L. J.Z. and J-D.L. wrote and revised the manuscript with contributions from all authors. H.L. contributed to the revision of the manuscript.

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Correspondence to Huadie Liu, Jing Zhang or Jia-Da Li.

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All methods in this study were performed in accordance with the relevant guidelines and regulations. All animal experiments were approved by the Ethics Committee of the School of Life Sciences, Central South University, China (Approval No. 2019-2-7). Consent to participate is not applicable as this study did not involve human participants.

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Li, X., Bader, I., Li, X. et al. Loss of Necdin causes social deficit and aberrant synaptic function through destabilization of SynGAP. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03187-7

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