Hippocampal PACAP signaling activation triggers a rapid antidepressant response.
Military Medical Research July 23, 2024 Hai-Lou Zhang, Yan Sun, Zhang-Jie Wu et al. 24 citations
The neuropeptide PACAP in the hippocampal dentate gyrus (DG) mediates rapid antidepressant responses. Chronic paroxetine increased hippocampal PACAP, and blocking PACAP in the DG slowed the antidepressant effect. PACAP levels were reduced in two depression models, and knocking down PACAP in the DG caused depression-like behaviors. A single infusion of PACAP into the DG produced a rapid and sustained antidepressant effect in normal and stressed mice. Optogenetic excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while inhibition induced depression-like behaviors. PACAP infusion inhibited CaMKII-eEF2 signaling and activated mTOR-BDNF signaling. Acute ketamine increased PACAP, and blocking PACAP attenuated ketamine's rapid antidepressant effect.