Impaired neuromodulator crosstalk delays arousal-dependent astroglia Ca2+ activation in mouse models of Alzheimer's disease.

Cortical astrocyte Ca2+ activation is associated with control of neuronal network activity and is altered in mouse models of Alzheimer's disease (AD). Applying enforced running, a well-controlled behavioral paradigm triggering arousal-mediated widespread Ca2+ activation in astroglia throughout the brain, to two mouse models of AD (APPswe/PSEN1dE9 and App NL-F KI), we consistently observed delayed and less coordinated astrocyte Ca2+ elevations. Combining pharmacological and genetic manipulations, we found that direct noradrenergic signaling to astrocytes was facilitated by cholinergic signaling, but this neuromodulator crosstalk was impaired in App NL-F mice. Pharmacological facilitation of norepinephrine release rescued delayed and less coordinated astrocyte Ca2+ activation in both mouse models and suggests that astrocytes preserve a functional reserve that can be recruited even during late-stage disease. Our findings demonstrate that impaired cholinergic facilitation of noradrenergic signaling in mouse models of AD contributes to altered astroglia Ca2+ activation and may represent a mechanism involved in cognitive decline.