1. Neuroscience
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Alzheimer's disease risk gene BIN1 induces Tau-dependent network hyperexcitability

Research Article
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Cite this article as: eLife 2020;9:e57354 doi: 10.7554/eLife.57354

Abstract

Genome-wide association studies identified the BIN1 locus as a leading modulator of genetic risk in Alzheimer's disease (AD). One limitation in understanding BIN1's contribution to AD is its unknown function in the brain. AD-associated BIN1 variants are generally noncoding and likely change expression. Here, we determined the effects of increasing expression of the major neuronal isoform of human BIN1 in cultured rat hippocampal neurons. Higher BIN1 induced network hyperexcitability on multielectrode arrays, increased frequency of synaptic transmission, and elevated calcium transients, indicating that increasing BIN1 drives greater neuronal activity. In exploring the mechanism of these effects on neuronal physiology, we found that BIN1 interacted with L-type voltage-gated calcium channels (LVGCCs) and that BIN1–LVGCC interactions were modulated by Tau in rat hippocampal neurons and mouse brain. Finally, Tau reduction prevented BIN1-induced network hyperexcitability. These data shed light on BIN1's neuronal function and suggest that it may contribute to Tau-dependent hyperexcitability in AD.

Article and author information

Author details

  1. Yuliya Voskobiynyk

    Neurology, Neurobiology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
  2. Jonathan R Roth

    Neurology, Neurobiology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8978-4507
  3. J Nicholas Cochran

    Neurology, Neurobiology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
  4. Travis Rush

    Neurology, Neurobiology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
  5. Nancy VN Carullo

    Neurology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9197-5046
  6. Jacob S Mesina

    Neurology, Neurobiology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
  7. Mohammad Waqas

    Neurology, Neurobiology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
  8. Rachael M Vollmer

    Neurology, Neurobiology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
  9. Jeremy J Day

    Department of Neurobiology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7361-3399
  10. Lori L McMahon

    Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1104-6584
  11. Erik D Roberson

    Neurology, Neurobiology, University of Alabama at Birmingham, Birmingham, United States
    For correspondence
    eroberson@uabmc.edu
    Competing interests
    Erik D Roberson, EDR is an owner of intellectual property relating to Tau.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1810-9763

Funding

National Institutes of Health (RF1AG059405)

  • Erik D Roberson

National Institutes of Health (R01NS075487)

  • Erik D Roberson

National Institutes of Health (R01MH114990)

  • Jeremy J Day

National Institutes of Health (T32NS095775)

  • Yuliya Voskobiynyk

National Institutes of Health (T32NS061788)

  • Jonathan R Roth

Alzheimer's Association

  • Erik D Roberson

Weston Brain Institute

  • Jonathan R Roth
  • Travis Rush
  • Erik D Roberson

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 performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20450) of the University of Alabama at Birmingham. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Alabama at Birmingham.

Reviewing Editor

  1. John D. Fryer, Mayo Clinic, United States

Publication history

  1. Received: March 29, 2020
  2. Accepted: July 12, 2020
  3. Accepted Manuscript published: July 13, 2020 (version 1)
  4. Version of Record published: July 30, 2020 (version 2)

Copyright

© 2020, Voskobiynyk et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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