Dentate gyrus’s role in the response to antidepressant treatment

Depression is a complex psychiatric disorder that is a major burden on society as 300 million people are diagnosed worldwide. Furthermore, only 33% of depressed patients achieve remission of symptoms upon initial monotherapy with commonly used selective serotonin reuptake inhibitors (SSRI). In preclinical studies using mice, chronic stress paradigms, such as chronic corticosterone and chronic social defeat stress, are used to induce negative valence behaviors. Chronic treatment with the SSRI fluoxetine (FLX) reverses these stress-induced behavioral changes in some, but not all mice, permitting stratification of mice into behavioral responders and non-responders to FLX. Recently, we reported that 5-HT1A receptors, which are Gi-coupled inhibitory receptors, on mature granule cells (GCs) in the dentate gyrus (DG), a subfield of the hippocampus, are necessary and sufficient for the behavioral, neurogenic, and neuroendocrine response to chronic SSRI treatment. Since inhibition of mature DG GCs through cell autonomous Gi-coupled receptors is critical for mounting an antidepressant response, we predicted that behavioral response to FLX would correlate with a decrease in DG GC activation and an increase in adult hippocampal neurogenesis compared to FLX non-responders and stress controls. Additionally, we wanted to assess whether chronic functional manipulation of DG GC activity via the usage of chemogenetics could mimic the effects of antidepressants. Our data shows that response to FLX treatment following chronic stress exposure leads to behavioral responders and non-responders across three distinct negative valence tasks (novelty suppressed feeding, elevated plus maze, and forced swim test). Intriguingly, behavioral responders show decreased DG GC activation (as measured by cFos immunostaining) and increased adult neurogenesis (as measured by Ki67 and DCX immunostaining) relative to stress only controls and non-responders. Furthermore, we show that chronic inhibition of ventral DG GCs (through usage of Gi-DREADDs) results in a decrease in negative valence behaviors. Taken together, these results illustrate that inhibition of DG GCs is a critical component of the response to antidepressants.M.S.Includes bibliographical referencesby Christine Yoh