Impaired astrocytic Ca2+ signaling in awake-behaving Alzheimer’s disease transgenic mice
Curation statements for this article:-
Curated by eLife
Evaluation Summary:
This manuscript is of broad interest to readers in the astrocyte and Alzheimer's Disease (AD) fields, and it utilizes state-of-the-art techniques to simultaneously record astrocyte calcium and animal behaviour. The work provides new insight into astrocyte calcium responses in AD, which has important implications for astrocyte pathophysiology. Overall, the data are of high quality and well analyzed.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Abstract
Increased astrocytic Ca 2+ signaling has been shown in Alzheimer’s disease mouse models, but to date no reports have characterized behaviorally induced astrocytic Ca 2+ signaling in such mice. Here, we employ an event-based algorithm to assess astrocytic Ca 2+ 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 Ca 2+ response to locomotion and an uncoupling of pupil responses and astrocytic Ca 2+ signaling in 15-month-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 Ca 2+ responses. Our data points to a dysfunction in the norepinephrine–astrocyte Ca 2+ activity axis, which may account for some of the cognitive deficits observed in Alzheimer’s disease.
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Evaluation Summary:
This manuscript is of broad interest to readers in the astrocyte and Alzheimer's Disease (AD) fields, and it utilizes state-of-the-art techniques to simultaneously record astrocyte calcium and animal behaviour. The work provides new insight into astrocyte calcium responses in AD, which has important implications for astrocyte pathophysiology. Overall, the data are of high quality and well analyzed.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Joint Public Review:
Strengths: The main strength of this study is the methods that were used. These techniques are at the forefront of the field. The authors combined two-photon calcium imaging with a genetically encoded sensor in astrocytes in the Tg-ArcSwe AD mouse line. Data was recorded from awake animals that were sitting on a running disk, so information was gathered from various behaviour states: quiet wakefulness, spontaneous running, and when startling the mouse with an air puff to the face. The sophisticated analytical tools developed by the authors were used to identify regions of astrocyte calcium activation in AD mice and controls for comparisons. This is the first study to examine astrocytes in awake, behaving Alzheimer's mice.
Weaknesses: Clearly lay out the goals of the study, providing sufficient description of all the …
Joint Public Review:
Strengths: The main strength of this study is the methods that were used. These techniques are at the forefront of the field. The authors combined two-photon calcium imaging with a genetically encoded sensor in astrocytes in the Tg-ArcSwe AD mouse line. Data was recorded from awake animals that were sitting on a running disk, so information was gathered from various behaviour states: quiet wakefulness, spontaneous running, and when startling the mouse with an air puff to the face. The sophisticated analytical tools developed by the authors were used to identify regions of astrocyte calcium activation in AD mice and controls for comparisons. This is the first study to examine astrocytes in awake, behaving Alzheimer's mice.
Weaknesses: Clearly lay out the goals of the study, providing sufficient description of all the various aspects-role of NA signaling in AD, NA induction of astrocytic Ca2+ signals, behavior-induced (NA-dependent) Ca2+ signals, novel technique for real-time monitoring of astrocytic Ca2+ signals, etc-for the reader to follow along. Provide a better description of the imaging processing and analysis procedures (including event-based detection aspect) in Methods so that the reader doesn't have to go to a previous publication to understand the basic workflow. Include better (or at least some) description of what panels illustrate in figure legends (see comments in Public Review). Provide statistics on regression analyses; a supplemental figure might be helpful in this regard. Consider using another read-out of NA activity that provides more reliable data than pupil responses (if available) or improve experimental procedures as necessary to reduce noise in pupil dilation data.
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