In addition to their support role in neurotransmitter and ion buffering, astrocytes directly regulate neurotransmission at synapses via local bidirectional signaling with neurons. Here, we reveal a form of neuronal-astrocytic signaling that transmits retrograde dendritic signals to distal upstream neurons in order to activate recurrent synaptic circuits. Norepinephrine activates a1 adrenoreceptors in hypothalamic corticotropin-releasing hormone (CRH) neurons to stimulate dendritic release, which triggers an astrocytic calcium response and release of ATP; ATP stimulates action potentials in upstream glutamate and GABA neurons to activate recurrent excitatory and inhibitory synaptic circuits to the CRH neurons. Thus, norepinephrine activates a retrograde signaling mechanism in CRH neurons that engages astrocytes in order to extend dendritic volume transmission to reach distal presynaptic glutamate and GABA neurons, thereby amplifying volume transmission mediated by dendritic release.

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