Long-term memory formation depends on an astrocyte-to-neuron H2O2 signaling

Astrocytes interact with neurons during cognitive processes[1][1]. In particular, astrocytes help neurons to fight oxidative stress[2][2], a needed function since active neurons are prone to reactive oxygen species (ROS) damage due to their high mitochondrial activity and relatively poor antioxidant defenses[3][3]. ROS also play major physiological functions[4][4],[5][5], but it remains unknown how neuronal ROS signaling is activated during memory formation and if astrocytes play a role in that process. We discovered in Drosophila an astrocyte-to-neuron H2O2 signaling cascade essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an intracellular calcium increase that triggers the formation of extracellular O2°− by astrocytic NADPH oxidase. Superoxide dismutase 3 secreted by astrocytes converts O2°− into H2O2, which is imported into neurons of the olfactory memory center (the mushroom body), as revealed by in vivo H2O2 imaging using an ultrasensitive sensor. Importantly, SOD3 activity requires Cu2+, which we show is delivered by the neuronal Amyloid Precursor Protein. Furthermore, we found that human amyloid-ß peptide, involved in Alzheimer’s disease, inhibits the astrocytic cholinergic receptor and hampers memory formation by preventing H2O2 import into neurons. These findings could have major implications for the understanding of Alzheimer’s disease etiology, as soluble synaptic Aß42 correlates better with the pattern of cognitive decline in AD than amyloid plaques[6][6], and since early pathology in cholinergic neurons of the basal forebrain predicts memory defects[7][7],[8][8]. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-8