Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour

Abstract

Summary Astrocytes associate with synapses throughout the brain and express receptors for neurotransmitters that can elevate intracellular calcium (Ca2+) 1-3. Astrocyte Ca2+ signaling has been proposed to modulate neural circuit activity 4, but pathways regulating these events are poorly defined and in vivo evidence linking changes in astrocyte Ca2+ to alterations in neurotransmission or behaviors is limited. Here we show Drosophila astrocytes exhibit activity-regulated Ca2+ signaling events in vivo. Tyramine (Tyr) and octopamine (Oct) released from Tdc2+ neurons signal directly to astrocytes to stimulate Ca2+ increases through the octopamine-tyramine receptor (Oct-TyrR) and the TRP channel Waterwitch (Wtrw), and astrocytes in turn modulate downstream dopaminergic (DA) neurons. Tyr or Oct application to live preparations silenced dopaminergic (DA) neurons and this inhibition required astrocytic Oct-TyrR and Wtrw. Increasing astrocyte Ca2+ signaling was sufficient to silence DA neuron activity, which was mediated by astrocyte endocytic function and adenosine receptors. Selective disruption of Oct-TyrR or Wtrw expression in astrocytes blocked astrocyte Ca2+ signaling and profoundly altered olfactory-driven chemotaxis behavior and touch-induced startle responses. Our work identifies Oct-TyrR and Wtrw as key components of the astrocyte Ca2+ signaling machinery, provides direct evidence that Oct- and Tyr-based neuromodulation can be mediated by astrocytes, and demonstrates that astrocytes are essential for multiple sensory-driven behaviors.

Does Global Astrocytic Calcium Signaling Participate in Awake Brain State Transitions and Neuronal Circuit Function?

“…Due to the slow time course of astrocytes, any immediate impact on neuronal responses would be expected to follow that time scale, or possibly create more long-term neuronal changes. This is interesting in context to a newly published study showing that astrocytic Ca 2+ signals, mediated by fly analog to neuromodulators, are directly involved in the regulation of neuronal activity and sensory-driven behaviors in drosophila flies [62]. However, direct comparisons to rodent studies should be undertaken with caution, since there are large differences in the species-specific cell and transmitter characteristics.…”

Cell Biology of Astrocyte-Synapse Interactions

“…Thus, both the nature and the function of astrocytic Ca 2+ -transients are likely to be distinct from that of neuronal Ca 2+ -signaling, which underlie fast synaptic transmission. In fact recent studies in Drosophila and mice have demonstrated that astrocytes respond to slow-acting neuromodulators such as norepinephrine, tyramine and octopamine with increases in intracellular calcium (Ding et al, 2013; Ma et al, 2016; Paukert et al, 2014). In Drosophila, astrocytic activation by octopamine/tyramine leads to inhibition of dopaminergic neuron firing and alterations in behavior, demonstrating an in vivo role for astrocyte calcium signaling in regulating neuronal circuit function (Ma et al, 2016).…”

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives

“…Animal studies increasingly highlight a role for oligodendrocytes in mood regulation (99). Astrocytes also influence microcircuit function through modulation of synaptic transmission via calcium signaling, release of glutamate and purinergic neurotransmitters, and neurotransmitter recycling (100). Further, circuit connectivity depends on the formation of functional neuronal assemblies mediated by astrocytes and microglia that are similarly altered in MDD.…”