Biophysical Kv3 channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer's

Abstract

In Alzheimer's disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disruptions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability, as they display altered AP firing before neighboring excitatory neurons in prodromal AD. Here we report a novel mechanism responsible for PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of Kv3 channels, but not changes in their mRNA or protein expression, were responsible for dampened excitability in young 5xFAD mice. These K+ conductances could efficiently regulate near-threshold AP firing, resulting in gamma-frequency specific network hyperexcitability. Thus biophysical ion channel alterations alone may reshape cortical network activity prior to changes in their expression levels. Our findings demonstrate an opportunity to design a novel class of targeted therapies to ameliorate cortical circuit hyperexcitability in early AD.

Data availability

We share access to our original code for simulations (single cell, reduced single cell in network, and layer 5 cortical network used in this manuscript for reviewers and the public here: https://github.com/ViktorJOlah/KDR-in-FS-PV. This code dataset has been made publicly available here: https://doi.org/10.5061/dryad.08kprr557For Mass Spec data, full source data has been provided for Supplementary Figure 4 (Related to Main figure 4).

The following data sets were generated

Article and author information

Author details

  1. Viktor J Olah

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2069-7525
  2. Annie M Goettemoeller

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sruti Rayaprolu

    Department of Neurology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Eric B Dammer

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Nicholas T Seyfried

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Srikant Rangaraju

    Department of Neurology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jordane Dimidschstein

    Stanley Center for Psychiatric Research, Broad Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Matthew JM Rowan

    Department of Cell Biology, Emory University, Atlanta, United States
    For correspondence
    mjrowan@emory.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0955-0706

Funding

National Institutes of Health (R56AG072473)

  • Matthew JM Rowan

National Institutes of Health (RF1AG062181)

  • Nicholas T Seyfried

National Institutes of Health (F32AG064862)

  • Sruti Rayaprolu

National Institutes of Health (R01MH111529)

  • Jordane Dimidschstein

National Institutes of Health (UG3MH120096)

  • Jordane Dimidschstein

Alzheimer's Disease Research Center, Emory University (00100569)

  • Matthew JM Rowan

National Institutes of Health (R01NS114130)

  • Srikant Rangaraju

National Institutes of Health (R01AG075820)

  • Srikant Rangaraju

National Institutes of Health (RF1AG071587)

  • Srikant Rangaraju

National Institutes of Health (RF1AG071587)

  • Nicholas T Seyfried

National Institutes of Health (R01AG061800)

  • Nicholas T Seyfried

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 Emory University institutional animal care and use committee (IACUC) protocols (#201800199). Every effort was made to reduce animal useage and to minimize suffering.

Reviewing Editor

  1. Inna Slutsky, Tel Aviv University, Israel

Publication history

  1. Received: November 5, 2021
  2. Accepted: May 19, 2022
  3. Accepted Manuscript published: June 21, 2022 (version 1)

Copyright

© 2022, Olah 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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  1. Viktor J Olah
  2. Annie M Goettemoeller
  3. Sruti Rayaprolu
  4. Eric B Dammer
  5. Nicholas T Seyfried
  6. Srikant Rangaraju
  7. Jordane Dimidschstein
  8. Matthew JM Rowan
(2022)
Biophysical Kv3 channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer's
eLife 11:e75316.
https://doi.org/10.7554/eLife.75316

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