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. Editor's summary: Astrocytes have been shown to modulate neuronal activity, and dysfunction in neuron-astrocyte communication causes alterations in many cognitive processes. However, the fundamental mechanisms by which astrocytes might be integrated into neuronal circuitry has remained largely unclear. Three independent studies investigated the mechanisms and molecular players involved in astrocyte-neuron communication using multiple in vivo and in vitro models (see the Perspective by Eroglu). Guttenplan et al. used fruit fly larvae and mammalian astrocyte cultures to show that exposure to the norepinephrine (NE) homolog tyramine enables astrocytes to suddenly respond potently to a range of neurotransmitters to which they are normally nonresponsive. In zebrafish, Chen et al. found that NE modulates larval behavior through NE receptor activation on astrocytes, astrocyte secretion of ATP, extracellular metabolism of ATP into adenosine, and activation of neuronal adenosine receptors. Finally, Lefton et al. showed that, in mice, NE modulates synaptic function through a signaling pathway involving astrocytic adrenergic receptors. These three studies point to a model of neural network function in which neuronal signaling and network function can be gated by computations in astrocytes. —Mattia Maroso [ABSTRACT FROM AUTHOR]