The Duality of Astrocyte Neuromodulation: Astrocytes Sense Neuromodulators and Are Neuromodulators

Neuromodulation encompasses different processes that regulate neuronal and network function. Classical neuromodulators originating from long-range nuclei, such as acetylcholine, norepinephrine, or dopamine, act with a slower time course and wider spatial range than fast synaptic transmission and action potential firing. Accumulating evidence in vivo indicates that astrocytes, which are known to actively participate in synaptic function at tripartite synapses, are also involved in neuromodulatory processes. The present article reviews recent findings obtained in vivo indicating that astrocytes express receptors for neuromodulators that elevate their internal calcium and stimulate the release of gliotransmitters, which regulate synaptic and network function, and hence mediate, at least partially, the effects of neuromodulators. In addition, we propose that astrocytes act in local support of neuromodulators by spatially and temporally integrating neuronal and neuromodulatory signals to regulate neural network function. The presence of astrocyte-neuron hysteresis loops suggests astrocyte–neuron interaction at tripartite synapses scales up to astrocyte–neuronal networks that modulate neural network function. We finally propose that astrocytes sense the environmental conditions, including neuromodulators and network function states, and provide homeostatic control that maximizes the dynamic range of neural network activity. In summary, we propose that astrocytes are critical in mediating the effects of neuromodulators, and they also act as neuromodulators to provide neural network homeostasis thus optimizing information processing in the brain. Hence, astrocytes sense ongoing neuronal activity along with neuromodulators and, acting as neuromodulators, inform the neurons about the state of the internal system and the external world. (Figure presented.)