Impaired astrocytic Ca2+ signaling in awake-behaving Alzheimer's disease transgenic mice

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Abstract

Increased astrocytic Ca²⁺ signaling has been shown in Alzheimer's disease mouse models, but to date no reports have characterized behaviorally induced astrocytic Ca²⁺ signaling in such mice. Here, we employ an event-based algorithm to assess astrocytic Ca²⁺ signals in the neocortex of awake-behaving tg-ArcSwe mice and non-transgenic wildtype littermates while monitoring pupil responses and behavior. We demonstrate an attenuated astrocytic Ca²⁺ response to locomotion and an uncoupling of pupil responses and astrocytic Ca²⁺ signaling in 15-months old plaque-bearing mice. Using the genetically encoded fluorescent norepinephrine sensor GRAB_NE we demonstrate a reduced norepinephrine signaling during spontaneous running and startle responses in the transgenic mice, providing a possible mechanistic underpinning of the observed reduced astrocytic Ca²⁺ responses. Our data points to a dysfunction in the norepinephrine-astrocyte Ca²⁺ activity-axis, which may account for some of the cognitive deficits observed in Alzheimer's disease.

Data availability

The numerical data for the statistical analyses in Figures 3-5 are available as Source Data File 1. The complete dataset is available at http://dx.doi.org/10.11582/2021.00100.

The following data sets were generated

1. Åbjørsbråten KS
2. Skaaraas GHES
3. Cunen C
4. Bjørnstad DM
5. Binder KMG
6. Jensen V
7. Nilsson LNG
8. Rao SB
9. Tang W
10. Hermansen GHH
11. Nagelhus EA
12. Ottersen OP
13. Torp R
14. Enger R
(2021) Impaired astrocytic Ca2+ signalling in awake Alzheimer's disease transgenic mice
NIRD, 10.11582/2021.00100.

http://dx.doi.org/10.11582/2021.00100

Article and author information

Author details

Knut Sindre Åbjørsbråten

Department of Molecular Medicine, University of Oslo, Oslo, Norway

Competing interests
The authors declare that no competing interests exist.
Gry HE Skaaraas

Department of Molecular Medicine, University of Oslo, Oslo, Norway

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The authors declare that no competing interests exist.
Céline Cunen

Department of Mathematics, University of Oslo, Oslo, Norway

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The authors declare that no competing interests exist.
Daniel M Bjørnstad

Department of Molecular Medicine, University of Oslo, Oslo, Norway

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The authors declare that no competing interests exist.
Kristin M Binder

Department of Molecular Medicine, University of Oslo, Oslo, Norway

Competing interests
The authors declare that no competing interests exist.
Laura Bojarskaite

Department of Molecular Medicine, University of Oslo, Oslo, Norway

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The authors declare that no competing interests exist.
Vidar Jensen

Department of Molecular Medicine, University of Oslo, Oslo, Norway

Competing interests
The authors declare that no competing interests exist.
Lars NG Nilsson

Department of Pharmacology, University of Oslo, Oslo, Norway

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The authors declare that no competing interests exist.
Shreyas B Rao

Department of Molecular Medicine, University of Oslo, Oslo, Norway

Competing interests
The authors declare that no competing interests exist.
Wannan Tang

Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

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The authors declare that no competing interests exist.
Gudmund Horn Hermansen

Department of Mathematics, University of Oslo, Oslo, Norway

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The authors declare that no competing interests exist.
Erlend A Nagelhus

Department of Pharmacology, University of Oslo, Oslo, Norway

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The authors declare that no competing interests exist.
Ole Petter Ottersen

Office of the President, Karolinska Institute, Stockholm, Sweden

Competing interests
The authors declare that no competing interests exist.
Reidun Torp

Department of Molecular Medicine, University of Oslo, Oslo, Norway

Competing interests
The authors declare that no competing interests exist.
Rune Enger

Department of Molecular Medicine, University of Oslo, Oslo, Norway

For correspondence
rune.enger@medisin.uio.no

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9418-7117

Funding

Norges Forskningsråd (Grant 249988)

Rune Enger

Norges Forskningsråd (Grant 302326)

Rune Enger

Letten Foundation (Research support)

Rune Enger

Olav Thon Stiftelsen (Olav Thon Award)

Erlend A Nagelhus

Helse Sør-Øst RHF (Grant 2016070)

Rune Enger

Norges Forskningsråd (Medical Student Research Program)

Kristin M Binder

Helse Sør-Øst RHF (2020039)

Rune Enger

Norges Forskningsråd (Grant 271555/F20)

Kristin M Binder

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

Ethics

Animal experimentation: The study was performed in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and approved by the Norwegian Food Safety Authority (project number: FOTS #11983).

Copyright

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.