Impaired astrocytic Ca 2+ signaling in awake-behaving Alzheimer's disease transgenic mice

Increased astrocytic Ca signaling has been shown in Alzheimer's disease mouse models, but to date no reports have characterized behaviorally induced astrocytic Ca signaling in such mice. Here, we employ an event-based algorithm to assess astrocytic Ca 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 response to locomotion and an uncoupling of pupil responses and astrocytic Ca signaling in 15-month-old plaque-bearing mice. Using the genetically encoded fluorescent norepinephrine sensor GRAB , 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 responses. Our data points to a dysfunction in the norepinephrine-astrocyte Ca activity axis, which may account for some of the cognitive deficits observed in Alzheimer's disease.