Astrocytes, hidden puppet masters of the brain

It is accepted that neuromodulators such as norepinephrine and dopamine bind to and activate receptors on neurons to influence the activity of neuronal circuits and plasticity (changes in strength or wiring patterns) of synaptic connections, thus shaping the behavior of the organism. Unlike classical neurotransmitters (e.g., glutamate), which typically mediate fast, point-to-point synaptic communication, neuromodulators diffuse broadly through neural tissue to regulate the strength, duration, and plasticity of neuronal signaling. Emerging evidence now implicates astrocytes—traditionally seen as passive support cells—as active players in neuromodulation (1–3). However, whether astrocytes are necessary intermediaries in neuromodulation or represent regulatory adjuncts to neuronal actions is unclear. On pages 763, 769, and 776 of this issue, Guttenplan et al. (4), Chen et al. (5), and Lefton et al. (6), respectively, address these gaps in knowledge by reporting that astrocytes are indispensable for neuromodulatory signaling across diverse neural circuits, behavioral contexts, and species.