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).
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Biophysical Kv channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer'sDryad Digital Repository, doi:10.5061/dryad.08kprr557.
Article and author information
Author details
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.
Reviewing Editor
- Inna Slutsky, Tel Aviv University, Israel
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.
Version history
- Preprint posted: October 26, 2021 (view preprint)
- Received: November 5, 2021
- Accepted: May 19, 2022
- Accepted Manuscript published: June 21, 2022 (version 1)
- Version of Record published: July 13, 2022 (version 2)
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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