Neuropeptide-mediated activation of astrocytes improves stress resilience in mice by modulating cortical neural synapses.

Astrocytes are known to modulate synaptogenesis or neuronal activities, thus participating in mental functions. It has been shown that astrocytes are involved in the antidepressant mechanism. In this study we investigated the potential hormonal mediator governing the astrocyte-neuron interplay for stress-coping behaviors. Mice were subjected to chronic restraint stress (CRS) for 14 days, and then brain tissue was harvested for analyses. We found that the expression of pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor PAC1 was significantly decreased in astrocytes of the prelimbic (PrL) cortex. By conducting a combination of genetics, in vivo imaging and behavioral assays we demonstrated that PAC1 in cortical astrocytes was necessary for maintaining normal resilience of mice against chronic environmental stress like restraint stress. Furthermore, we showed the enhancement of de novo cortical spine formation and synaptic activity under PACAP-mediated astrocytic activation possibly via the ATP release. The molecular mechanisms suggested that the vesicle homeostasis mediated by PACAP-PAC1 axis in astrocytes was involved in regulating synaptic functions. This study identifies a previously unrecognized route by which neuropeptide modulates cortical functions via local regulation of astrocytes.