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

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.