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 <i>App</i> ^<i>NL-F</i> <i>KI</i>), 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 <i>App</i> ^<i>NL-F</i> 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.