Abstract

Neurotransmission requires precise control of neurotransmitter release from axon terminals. This process is regulated by glial cells; however, the underlying mechanisms are not fully understood. We found that glutamate release in the brain was impaired in mice lacking low-density lipoprotein receptor–related protein 4 (Lrp4), a protein that is critical for neuromuscular junction formation. Electrophysiological studies revealed compromised release probability in astrocyte-specific Lrp4 knockout mice. Lrp4 mutant astrocytes suppressed glutamatergic transmission by enhancing the release of ATP, whose level was elevated in the hippocampus of Lrp4 mutant mice. Consequently, the mutant mice were impaired in locomotor activity and spatial memory and were resistant to seizure induction. These impairments could be ameliorated by blocking the adenosine A1 receptor. The results reveal a critical role for Lrp4, in response to agrin, in modulating astrocytic ATP release and synaptic transmission. Our findings provide insight into the interaction between neurons and astrocytes for synaptic homeostasis and/or plasticity.

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Acknowledgements

We are grateful to W.-P. Ge (UT Southwestern Medical Center) and K.D. McCarthy (University of North Carolina) for GFAP::CreER mice. We thank members of the Mei and Xiong laboratories for helpful discussions. This work was supported in part by grants from the US National Institutes of Health (L.M., W.-C.X.) and Veterans Affairs (L.M., W.-C.X.), “Thousand Talents” Innovation Project from Jiangxi Province (L.M.), National Natural Science Foundation of China (NSFC, 81471116, B.-M.L), NSFC (81329003; U1201225; 31430032, T.-M.G.), Guangzhou Science and Technology Project (201300000093, T.-M.G.) and Specialized Research Fund for the Doctoral Program of Higher Education of China (20134433130002, T.-M.G.).

Author information

Author notes

    • Xiang-Dong Sun
    •  & Lei Li

    These authors contributed equally to this work.

Affiliations

  1. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.

    • Xiang-Dong Sun
    • , Lei Li
    • , Fang Liu
    • , Zhi-Hui Huang
    • , Jonathan C Bean
    • , Arnab Barik
    • , Seon-Myung Kim
    • , Haitao Wu
    • , Chengyong Shen
    • , Yun Tian
    • , Thiri W Lin
    • , Ryan Bates
    • , Anupama Sathyamurthy
    • , Yong-Jun Chen
    • , Dong-Min Yin
    • , Lei Xiong
    • , Hui-Ping Lin
    • , Jin-Xia Hu
    • , Wen-Cheng Xiong
    •  & Lin Mei
  2. Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang, China.

    • Hui-Feng Jiao
    • , Bao-Ming Li
    •  & Lin Mei
  3. Jiangxi Medical School, Nanchang University, Nanchang, China.

    • Bao-Ming Li
    •  & Lin Mei
  4. State Key Laboratory of Organ Failure Research, Key Laboratory of Psychiatric Disorders of Guangdong Province, Department of Neurobiology, Southern Medical University, Guangzhou, China.

    • Tian-Ming Gao
  5. Charlie Norwood Virginia Medical Center, Augusta, Georgia, USA.

    • Wen-Cheng Xiong
    •  & Lin Mei

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Contributions

X.-D.S. and L.M. conceived, designed and directed the project, and wrote the manuscript. X.-D.S performed electrophysiological recordings and analysis. L.L. conducted immunoblots, quantitative reverse-transcription PCR (qRT-PCR) and co-immunoporecipitation. F.L., R.B., A.B. and A.S. conducted Golgi staining, X-gal staining, immunofluorescence staining and analysis. Z.-H.H. conducted immunoblots and astrocyte culture experiments and analysis. J.C.B. performed behavioral tests and microdialysis analysis, with the assistance of Y.-J.C. and D.-M.Y. H.-F.J., S.-M.K. and Y.T. conducted cell culture experiments and analysis. H.W. and C.S., provided and assisted with characterization of Lrp4 mutant mice. T.W.L. conducted spine and synapse analysis. L.X., H.-P.L., J.-X.H. assisted with breeding and genotyping Lrp4 mutant lines. B.-M.L., T.-M.G. and W.-C.X. helped with data interpretation and provided instruction. L.M. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Xiang-Dong Sun or Lin Mei.

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