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.