Impaired neuromodulator crosstalk delays arousal-dependent astroglia Ca(2+) activation in mouse models of Alzheimer's disease.

Cortical astrocyte Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) activation and may represent a mechanism involved in cognitive decline.