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

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-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 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.

SUBMITTER: Abjorsbraten KS

PROVIDER: S-EPMC9352348 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Åbjørsbråten Knut Sindre KS Skaaraas Gry H E Syverstad GHES Cunen Céline C Bjørnstad Daniel M DM Binder Kristin M Gullestad KMG Bojarskaite Laura L Jensen Vidar V Nilsson Lars N G LNG Rao Shreyas B SB Tang Wannan W Hermansen Gudmund Horn GH Nagelhus Erlend A EA Ottersen Ole Petter OP Torp Reidun R Enger Rune R

eLife 20220714

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 ...[more]

PMID: 35833623

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Project description:Epilepsy is a group of neurological disorders commonly associated with the neuronal malfunction leading to generation of seizures. Recent reports point to a possible contribution of astrocytes into this pathology. We used the lithium-pilocarpine model of status epilepticus (SE) in rats to monitor changes in astrocytes. Experiments were performed in acute hippocampal slices 2-4 weeks after SE induction. Nissl staining revealed significant neurodegeneration in the pyramidal cell layers of hippocampal CA1, CA3 areas, and the hilus, but not in the granular cell layer of the dentate gyrus. A significant increase in the density of astrocytes stained with an astrocyte-specific marker, sulforhodamine 101, was observed in CA1 stratum (str.) radiatum. Astrocytes in this area were also whole-cell loaded with a morphological tracer, Alexa Fluor 594, for two-photon excitation imaging. Sholl analyses showed no changes in the size of the astrocytic domain or in the number of primary astrocytic branches, but a significant reduction in the number of distal branches that are resolved with diffraction-limited light microscopy (and are thought to contain Ca2+ stores, such as mitochondria and endoplasmic reticulum). The atrophy of astrocytic branches correlated with the reduced size, but not overall frequency of Ca2+ events. The volume tissue fraction of nanoscopic (beyond the diffraction limit) astrocytic leaflets showed no difference between control and SE animals. The results of spatial entropy-complexity spectrum analysis were also consistent with changes in ratio of astrocytic branches vs. leaflets. In addition, we observed uncoupling of astrocytes through the gap-junctions, which was suggested as a mechanism for reduced K+ buffering. However, no significant difference in time-course of synaptically induced K+ currents in patch-clamped astrocytes argued against possible alterations in K+ clearance by astrocytes. The magnitude of long-term-potentiation (LTP) was reduced after SE. Exogenous D-serine, a co-agonist of NMDA receptors, has rescued the initial phase of LTP. This suggests that the reduced Ca2+-dependent release of D-serine by astrocytes impairs initiation of synaptic plasticity. However, it does not explain the failure of LTP maintenance which may be responsible for cognitive decline associated with epilepsy.

Dataset Information

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

Publications

Impaired astrocytic Ca<sup>2+</sup> signaling in awake-behaving Alzheimer's disease transgenic mice.

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