5-HT_1A Receptors on Dentate Gyrus Granule Cells Confer Stress Resilience

Hyperactivity of granule cells in the ventral dentate gyrus (vDG) promotes vulnerability to chronic stress. However, which receptors in the vDG could be targeted to inhibit this hyperactivity and confer stress resilience is not known. The serotonin 1A receptor (5-HT_1AR) is a G_i protein-coupled inhibitory receptor that has been implicated in stress adaptation, anxiety, depression, and antidepressant responses. 5-HT_1ARs are highly expressed in the DG, but their potential to promote stress resilience by regulating granule cell activity has never been examined.

We exposed male and female mice expressing 5-HT_1ARs only in DG granule cells to 10 days of chronic social defeat stress (CSDS) and treated them with the 5-HT_1AR agonist 8-OH-DPAT every day 30 minutes before each defeat throughout the CSDS paradigm. We then used whole-cell current clamp recordings, immunohistochemistry for the immediate early gene cFos, corticosterone immunoassays, and behavioral testing to determine how activating 5-HT_1ARs on granule cells affects DG activity, neuroendocrine stress responses, and avoidance behavior.

We found that activating 5-HT_1ARs hyperpolarized DG granule cells and reduced cFos+ granule cells in the vDG following CSDS, indicating that 5-HT_1AR activation rescued stress-induced vDG hyperactivity. Moreover, 5-HT_1AR activation dampened corticosterone responses to CSDS and prevented the development of stress-induced avoidance in the social interaction test and in the open field test.

Our findings show that activating 5-HT_1ARs on DG granule cells can prevent stress-induced neuronal hyperactivity of the vDG and confer resilience to chronic stress.