1. Neuroscience
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APP modulates KCC2 expression and function in hippocampal GABAergic inhibition

  1. Ming Chen
  2. Jinzhao Wang
  3. Jinxiang Jiang
  4. Xingzhi Zheng
  5. Nicholas J Justice
  6. Kun Wang
  7. Yi Li
  8. Xiangqian Ran
  9. Qingwei Huo
  10. Jiajia Zhang
  11. Hongmei Li
  12. Nannan Lu
  13. Ying Wang
  14. Hui Zheng
  15. Cheng Long
  16. Li Yang  Is a corresponding author
  1. South China Normal University, China
  2. University of Texas Health Sciences Center, United States
  3. South China Normal University, United States
  4. Baylor College of Medicine, United States
Research Article
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Cite this article as: eLife 2017;6:e20142 doi: 10.7554/eLife.20142

Abstract

Amyloid precursor protein (APP) is enriched at the synapse, but its synaptic function is still poorly understood. We previously showed that GABAergic short-term plasticity is impaired in App knock-out (App-/-) animals, but the precise mechanism by which APP regulates GABAergic synaptic transmission has remained elusive. Using electrophysiological, biochemical, moleculobiological, and pharmacological analysis, here we show that APP can physically interact with KCC2, a neuron-specific K+-Cl- cotransporter that is essential for Cl- homeostasis and fast GABAergic inhibition. APP deficiency results in significant reductions in both total and membrane KCC2 levels, leading to a depolarizing shift in the GABA reversal potential (EGABA). Simultaneous measurement of presynaptic action potentials and inhibitory postsynaptic currents (IPSCs) in hippocampal neurons reveals impaired unitary IPSC amplitudes attributable to a reduction in α1 subunit levels of GABAAR. Importantly, restoration of normal KCC2 expression and function in App-/- mice rescues EGABA, GABAAR α1 levels and GABAAR mediated phasic inhibition. We show that APP functions to limit tyrosine-phosphorylation and ubiquitination and thus subsequent degradation of KCC2, providing a mechanism by which APP influences KCC2 abundance. Together, these experiments elucidate a novel molecular pathway in which APP regulates, via protein-protein interaction with KCC2, GABAAR mediated inhibition in the hippocampus.

Article and author information

Author details

  1. Ming Chen

    School of Life Sciences, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Jinzhao Wang

    School of Life Sciences, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Jinxiang Jiang

    School of Psychology, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Xingzhi Zheng

    School of Life Sciences, South China Normal University, Guang Zhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Nicholas J Justice

    Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kun Wang

    School of Life Sciences, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yi Li

    School of Life Sciences, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiangqian Ran

    School of Life Sciences, South China Normal University, Guangzhou, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Qingwei Huo

    School of Life Sciences, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Jiajia Zhang

    School of Life Sciences, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Hongmei Li

    Huffington Center on Aging, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Nannan Lu

    School of Life Sciences, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Ying Wang

    School of Life Sciences, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Hui Zheng

    Huffington Center on Aging, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Cheng Long

    School of Life Sciences, South China Normal University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Li Yang

    School of Psychology, South China Normal University, Guangzhou, China
    For correspondence
    yang_li@m.scnu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7448-8588

Funding

National Natural Science Foundation of China (31171018,31171355)

  • Cheng Long
  • Li Yang

Natural Science Foundation of Guangdong Province (2014A030313418,2014A030313440)

  • Cheng Long
  • Li Yang

The Science and Technology Division of Guangdong Province (2013KJCX0054,201607010320)

  • Li Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was conducted along the guidelines described in "The Guide for the Care and Use of Laboratory Animals" (Eighth Edition). All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#0312-11) of the South China Normal University. Every effort was made to minimize suffering.

Reviewing Editor

  1. Eunjoon Kim, Institute for Basic Science, Korea Advanced Institute of Science and Technology, Republic of Korea

Publication history

  1. Received: July 28, 2016
  2. Accepted: December 16, 2016
  3. Accepted Manuscript published: January 5, 2017 (version 1)
  4. Version of Record published: January 10, 2017 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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