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Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice

Molecular Psychiatry (2024)Cite this article

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Abstract

The pathophysiology of autism spectrum disorders (ASDs) is causally linked to postsynaptic scaffolding proteins, as evidenced by numerous large-scale genomic studies [1, 2] and in vitro and in vivo neurobiological studies of mutations in animal models [3, 4]. However, due to the distinct phenotypic and genetic heterogeneity observed in ASD patients, individual mutation genes account for only a small proportion (<2%) of cases [1, 5]. Recently, a human genetic study revealed a correlation between de novo variants in FERM domain-containing-5 (FRMD5) and neurodevelopmental abnormalities [6]. In this study, we demonstrate that deficiency of the scaffolding protein FRMD5 leads to neurodevelopmental dysfunction and ASD-like behavior in mice. FRMD5 deficiency results in morphological abnormalities in neurons and synaptic dysfunction in mice. Frmd5-deficient mice display learning and memory dysfunction, impaired social function, and increased repetitive stereotyped behavior. Mechanistically, tandem mass tag (TMT)-labeled quantitative proteomics revealed that FRMD5 deletion affects the distribution of synaptic proteins involved in the pathological process of ASD. Collectively, our findings delineate the critical role of FRMD5 in neurodevelopment and ASD pathophysiology, suggesting potential therapeutic implications for the treatment of ASD.

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Fig. 1: Knockout of Frmd5 leads to ASD-like behavioral abnormalities in mice.
Fig. 2: Knockout of Frmd5 leads to abnormal dendritic branching in the basal CA1 region and abnormal spine morphology.
Fig. 3: Knockout of Frmd5 leads to increased intrinsic excitability in granule cells of the DG.
Fig. 4: Molecular changes in the synaptosome of Frmd5−/− mice.

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Data availability

Data from this study are available from the authors upon reasonable request.

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Acknowledgements

This work was supported by the Ministry of Science and Technology of China (2021ZD0203204, 2022YFA1104003 and 2021YFC2501003) and grants from the National Natural Science Foundation of China (32030052, 31530028, 31720103908, 82230094, 81621063 and 81972616).

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Author notes

  1. These authors contributed equally: Tian-Jie Lyu, Ji Ma, Xi-Yin Zhang, Guo-Guang Xie, Cheng Liu, Juan Du.

Authors and Affiliations

  1. Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, National Health Commission and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 100191, Beijing, China

    Tian-Jie Lyu, Xi-Yin Zhang, Guo-Guang Xie, Yi-Nuo Xu, Cheng Cen, Na-Yun Lyu & Yun Wang

  2. Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, State Key Laboratory of Molecular Oncology and International Cancer Institute, Peking University Health Science Center, 100191, Beijing, China

    Ji Ma, Cheng Liu, Juan Du, De-Cao Yang, Meng-Yuan Wang & Hong-Quan Zhang

  3. PKU-IDG/McGovern Institute for Brain Research, Peking University, 100871, Beijing, China

    Yun Wang

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Contributions

YW and HQZ conceived and supervised the project. JD and JM performed the generation and breeding of the Frmd5 knock-out mice; TJL, JM, CL, DCY, XYZ, MYW performed the behavioral, molecular and biochemical experiments; GGX, CC and NYL performed electrophysiological and morphological experiments; TJL and CL performed the proteomics experiments; XYZ, TJL, JM and YNX wrote the manuscript. All of the authors read and accepted the manuscript.

Corresponding authors

Correspondence to Yun Wang or Hong-Quan Zhang.

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The authors declare no competing interests.

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All animal procedures performed in this study were approved by the Ethics Committee of Peking University Health Science Center (Beijing, China). For the data from the Decipher project, those who carried out the original analysis and collection of the data bear no responsibility for the further analysis or interpretation of the data.

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Lyu, TJ., Ma, J., Zhang, XY. et al. Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02407-w

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