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Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of fragile X mental retardation protein in neurotransmission

Authors

  • Xiao-Sheng Wang,

    1. Department of Histology and Embryology, Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha 410013, China
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  • Chun-Zi Peng,

    1. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
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  • Wei-Jun Cai,

    1. Department of Histology and Embryology, Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha 410013, China
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  • Jian Xia,

    1. Institute of Neurology, Xiangya Hospital, Central South University, Changsha, China
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  • Daozhong Jin,

    1. Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA
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  • Yuqiao Dai,

    1. Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
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  • Xue-Gang Luo,

    1. Department of Histology and Embryology, Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha 410013, China
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  • Vitaly A. Klyachko,

    Corresponding author
    1. Department of Cell Biology and Physiology, Department of Biomedical Engineering, Washington University School of Medicine, St Louis, MO, USA
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  • Pan-Yue Deng

    Corresponding author
    1. Department of Histology and Embryology, Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha 410013, China
    2. Department of Cell Biology and Physiology, Department of Biomedical Engineering, Washington University School of Medicine, St Louis, MO, USA
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Abstract

Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and mechanisms of these FMRP actions remain incompletely understood, and the role of FMRP in regulating synaptic release probability and presynaptic function remains debated. Here we used variance-mean analysis and peak-scaled nonstationary variance analysis to examine changes in both presynaptic and postsynaptic parameters during repetitive activity at excitatory CA3–CA1 hippocampal synapses in a mouse model of FXS. Our analyses revealed that loss of FMRP did not affect the basal release probability or basal synaptic transmission, but caused an abnormally elevated release probability specifically during repetitive activity. These abnormalities were not accompanied by changes in excitatory postsynaptic current kinetics, quantal size or postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor conductance. Our results thus indicate that FMRP regulates neurotransmission at excitatory hippocampal synapses specifically during repetitive activity via modulation of release probability in a presynaptic manner. Our study suggests that FMRP function in regulating neurotransmitter release is an activity-dependent phenomenon that may contribute to the pathophysiology of FXS.

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