Dentate nNOS accounts for stress-induced 5-HT_1A receptor deficiency: Implication in anxiety behaviors

Anxiety is a common disorder with high social burden worldwide. Dysfunction of serotonin-_1A receptor (5-HT_1A receptor) in the dentate gyrus (DG) of the hippocampus has been predominantly implicated in the anxiety behavior. However, the molecular mechanism underlying the deficiency of postsynaptic 5-HT_1A receptor in regulating anxiety behavior remains unclear.

Using pharmacological and genetic methods, we investigated the role of detate nNOS in 5-HT_1A receptor decline and anxiety behavior induced by chronic mild stress (CMS) in mice.

Here we showed that local elevation of glucocorticoids in the DG accounted for chronic stress-induced anxiety behavior. Neuronal nitric oxide synthase (nNOS) mediated chronic stress-induced downregulation of 5-HT_1A receptor in the DG through peroxynitrite anion (ONOO•) pathway but not cyclic guanosine monophosphate (cGMP) pathway. By using pharmacological tool drugs and nNOS knockout mice, we found that nNOS in the DG played a key role in chronic stress-induced anxiety behavior.

These findings uncovered an important role of nNOS-5-HT_1A receptor pathway in the DG of the hippocampus in chronic stress-induced anxiety. Accordingly, we developed a "dentate nNOS-5-HT_1A receptor closed-loop" theory (stress-glucocorticoids-nNOS-Nitric oxide-ONOO•-5-HT_1A receptor -nNOS) of stress-related anxiety.