Seipin regulates excitatory synaptic transmission in cortical neurons

Authors

  • Shunhui Wei,

    1. Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore
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  • Stephanie Li-Ying Soh,

    1. Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore
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  • Wenjie Qiu,

    1. Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore
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  • Wulin Yang,

    1. Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore
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  • Cheyenne Jia-Yan Seah,

    1. Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore
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  • Jing Guo,

    1. Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore
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  • Wei-Yi Ong,

    1. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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  • Zhiping P. Pang,

    Corresponding author
    1. Child Health Institute of New Jersey, New Brunswick, NJ, USA
    2. Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA
    • Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore
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  • Weiping Han

    Corresponding author
    1. Institute of Molecular and Cell Biology, A*STAR, Singapore
    2. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    3. Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore
    • Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore
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Address correspondence and reprint requests to Weiping Han, #02-02 Helios, 11 Biopolis Way, Singapore 138667 or Zhiping Pang, 89 French Street, New Brunswick, NJ 08901, USA. E-mails: pangzh@umdnj.edu; weiping_han@sbic.a-star.edu.sg

Abstract

Heterozygosity for missense mutations in Seipin, namely N88S and S90L, leads to a broad spectrum of motor neuropathy, while a number of loss-of-function mutations in Seipin are associated with the Berardinelli–Seip congenital generalized lipodystrophy type 2 (CGL2, BSCL2), a condition that is characterized by severe lipoatrophy, insulin resistance, and intellectual impairment. The mechanisms by which Seipin mutations lead to motor neuropathy, lipodystrophy, and insulin resistance, and the role Seipin plays in central nervous system (CNS) remain unknown. The goal of this study is to understand the functions of Seipin in the CNS using a loss-of-function approach, i.e. by knockdown (KD) of Seipin gene expression. Excitatory post-synaptic currents (EPSCs) were impaired in Seipin-KD neurons, while the inhibitory post-synaptic currents (IPSCs) remained unaffected. Expression of a shRNA-resistant human Seipin rescued the impairment of EPSC produced by Seipin KD. Furthermore, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced whole-cell currents were significantly reduced in Seipin KD neurons, which could be rescued by expression of a shRNA-resistant human Seipin. Fluorescent imaging and biochemical studies revealed reduced level of surface AMPA receptors, while no obvious ultrastructural changes in the pre-synapse were found. These data suggest that Seipin regulates excitatory synaptic function through a post-synaptic mechanism.

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