Amygdala-hippocampal innervation modulates stress-induced depressive-like behaviors through AMPA receptors.

Chronic stress is one of the most critical factors in the onset of depressive disorders; hence, environmental factors such as psychosocial stress are commonly used to induce depressive-​like traits in animal models of depression. Ventral CA1 (vCA1) in hippocampus and basal lateral amygdala (BLA) are critical sites during chronic stress-induced alterations in depressive subjects; however, the underlying neural mechanisms remain unclear. Here we employed chronic unpredictable mild stress (CUMS) to model depression in mice and found that the activity of the posterior BLA to vCA1 (pBLA-vCA1) innervation was markedly reduced. Mice subjected to CUMS showed reduction in dendritic complexity, spine density, and synaptosomal AMPA receptors (AMPARs). Stimulation of pBLA-vCA1 innervation via chemogenetics or administration of cannabidiol (CBD) could reverse CUMS-induced synaptosomal AMPAR decrease and efficiently alleviate depressive-like behaviors in mice. These findings demonstrate a critical role for AMPARs and CBD modulation of pBLA-vCA1 innervation in CUMS-induced depressive-like behaviors.