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

Cortical astrocyte Ca 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 activation in astroglia throughout the brain, to two mouse models of AD (APPswe/PSEN1dE9 and ), we consistently observed delayed and less coordinated astrocyte Ca 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 mice. Pharmacological facilitation of norepinephrine release rescued delayed and less coordinated astrocyte Ca 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 activation and may represent a mechanism involved in cognitive decline.