Norepinephrine signals through astrocytes to modulate synapses

Locus ceruleus (LC)–derived norepinephrine (NE) drives network and behavioral adaptations to environmental saliencies by reconfiguring circuit functional connectivity, but the underlying synapse-level mechanisms are elusive. Here, we show that NE remodeling of synaptic function is completely independent from its binding on neuronal receptors. Instead, astrocytic adrenergic receptors and calcium dynamics fully gate the effect of NE on synapses. Additionally, we found that NE suppression of synaptic strength results from an adenosine 5′-triphosphate (ATP)–derived and A1 adenosine receptor–mediated control of presynaptic efficacy. These findings suggest that astrocytes are a core component of neuromodulatory systems and the circuit effector through which NE produces network and behavioral adaptations.