5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is unknown whether the mature dentate gyrus granule cells (mature DG GCs) also contribute. We deleted Serotonin 1A receptor (5HT1AR; a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the Hypothalamic-Pituitary-Adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult born granule cells (abGCs) showed normal fluoxetine responses. Importantly, 5HT1AR deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response.

Adult hippocampal neurogenesis and cognitive flexibility — linking memory and mood

“…However, the clinical challenge remains to specifically target this defined population of adult-born cells pharmacologically. It is important to note in this context that the effects of SSRIs are, at least in part, mediated by serotonin 1A receptors (5HT1 ARs) that are located on mature granule cells but not on young adult-born neurons 158 . Whether these 5HTlAR-dependent effects of SSRIs are mediated by enhanced neurogenesis that results from the 5HT1AR-dependent release of neurotrophic factors from mature granule cells remains to be elucidated 158 .…”

“…It is important to note in this context that the effects of SSRIs are, at least in part, mediated by serotonin 1A receptors (5HT1 ARs) that are located on mature granule cells but not on young adult-born neurons 158 . Whether these 5HTlAR-dependent effects of SSRIs are mediated by enhanced neurogenesis that results from the 5HT1AR-dependent release of neurotrophic factors from mature granule cells remains to be elucidated 158 . Of note, 5HT1ARs are G i protein-coupled receptors that silence neuronal activity by opening G protein-coupled inward-rectifying potassium (GIRK) channels 159 .…”

Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior

“…of Ottawa). The TPH2-Cre-ERT2/ Freud-1wt/flx were crossed with fl1A mice (C57BL/6 × 129Sv × ROSA-Flpe background) (Szewczyk et al, 2014;Samuels et al, 2015) and bred to obtain TPH2-CreERT2-Freud-1flx/flx/1Aflx/flx mice (cF1/1Adko) (Fig. 1A).…”

“…For SSRI treatment, a separate cohort of mice, including conditional Freud-1 knockout and WT littermates (11 wk old, n=10), was single housed and received 18 mg/kg/day fluoxetine hydrochloride (Santarelli et al, 2003;Samuels et al, 2015) (Enzo life science, cat#BML-NS140-0250, Farmingdale, NY, USA) in drinking water for 3-4 weeks using opaque bottles to protect the SSRI from light. Then, several behavioral tests were done as described above, with ongoing SSRI treatment, following the timeline shown in Figure 4.…”

“…To address whether the behavioral phenotype induced by loss of Freud-1 is dependent on the increased level of 5-HT1A autoreceptors, the cF1ko mice were mated to the flx-1A mice (Samuels et al, 2015), in which the 5-HT1A gene is flanked by LoxP sites and a YFP cassette ( Figure 1A). Tamoxifen-induced recombination in 5-HT neurons in cF1/1Adko mice was verified by co-staining for YFP and TPH ( Figure 5A).…”