5-HT1A Receptors on Dentate Gyrus Granule Cells Confer Stress Resilience

Background 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 (5HT1AR) is a Gi protein coupled inhibitory receptor that has been implicated in stress adaptation, anxiety, depression, and antidepressant responses. 5HT1ARs are highly expressed in the DG, but their potential to promote stress resilience by regulating granule cell activity has never been examined. Methods We exposed male and female mice expressing 5HT1ARs only in DG granule cells to 10 days of chronic social defeat stress (CSDS) and treated them with the 5HT1AR agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) every day 30 min 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 5HT1ARs on granule cells affects DG activity, neuroendocrine stress responses, and avoidance behavior. Results We find that activating 5HT1ARs hyperpolarizes DG granule cells and reduces cFos+ granule cells in the vDG following CSDS, indicating that 5HT1AR activation rescues stress-induced vDG hyperactivity. Moreover, 5HT1AR activation dampens corticosterone responses to CSDS and prevents the development of stress-induced avoidance in the social interaction test and in the open field test. Conclusions Our findings show that activating 5HT1ARs on DG granule cells can prevent stress-induced neuronal hyperactivity of the vDG and confer resilience to chronic stress.