Abstract
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 new form of neuronal-astrocytic signaling that transmits retrograde dendritic signals to upstream neurons to activate recurrent synaptic circuits. Norepinephrine activates α1-adrenoreceptors in hypothalamic corticotropin releasing factor (CRF) 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 CRF neurons. Thus, norepinephrine activates a novel retrograde signaling mechanism in CRF 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.
Acknowledgments
This work was supported by NIH R01 MH069879 and the Catherine and Hunter Pierson Chair in Neuroscience. We thank Dr. Laura Harrison for her help with the animal husbandry and molecular analyses, and Dr. Diankun Yu for his helpful discussion of the paper. We thank Prof. Maurice Manning for his donation of vasopressin receptor antagonist and Dr. Paul Sawchenko for his donation of CRF antibody.
Author Contributions
C.C. and Z.J. contributed equally to the experiments, data analysis, and to writing the manuscript; X.F. contributed to the experiments and edition of the manuscript; J.G.T. contributed to the design and interpretation of experiments and to writing the manuscript.