Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment

Abstract

Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signaling mediate effects of antidepressant treatment on neural progenitor cell proliferation and behavior. Treatment with the selective serotonin reuptake inhibitor fluoxetine suppressed BMP signaling in the adult mouse hippocampus both by decreasing levels of BMP4 ligand and increasing production of the BMP inhibitor noggin. Increasing BMP signaling in the hippocampus via viral overexpression of BMP4 blocked the effects of fluoxetine on proliferation in the dentate gyrus and on depressive behavior. Conversely, inhibiting BMP signaling via viral overexpression of noggin in the hippocampus or infusion of noggin into the ventricles exerted antidepressant and anxiolytic activity along with an increase in hippocampal neurogenesis. Similarly, conditional genetic deletion of the type II BMP receptor in Ascl1-expressing cells promoted neurogenesis and reduced anxiety- and depression-like behaviors, suggesting that neural progenitor cells contribute to the effects of BMP signaling on affective behavior. These observations indicate that BMP signaling in the hippocampus regulates depressive behavior, and that decreasing BMP signaling may be required for the effects of some antidepressants. Thus BMP signaling is a new and powerful potential target for the treatment of depression.

Genetic liability for internalizing versus externalizing behavior manifests in the developing and adult hippocampus: Insight from a meta-analysis of transcriptional profiling studies in a selectively-bred rat model

“…Notably, the direction of effect in these gene sets changed between P14 and adulthood – at P14, gene sets related to proliferation and differentiation were enriched with elevated expression in bLRs, whereas by adulthood elevated expression was seen in bHRs. This pattern fits the changing role of Bmp4 across development: Bmp4 is important for neural induction during early development (102, 103), but later suppresses neurogenesis (100, 104–106) and promotes other cell fates (102, 107). For example, Bmp4 can a promote endothelial proliferation (84), which matches the elevated endothelial-specific gene expression that we observed in the bLR hippocampus at P14.…”

“…These results are consistent with the association between Bmp4 and anxiety and depressive-like behaviors in the literature. Blocking Bmp4 expression in mice reduces anxiety and depressive-like behavior and increases the effectiveness of certain anti-depressant treatments (100). Similarly, transgenic mice that are deficient for Bmp receptors have extremely low levels of anxiety and diminished fear conditioning (101).…”

Adult neurogenesis in the mammalian dentate gyrus

“…These NSCs undergo cell division, and some daughter cells differentiate into functional neurons that participate in learning and memory and general cognition through integration into pre‐existing neural networks (de Miranda, Zhang, Katsumoto, & Teixeira, ). Further evidence suggest that it is the dorsal hippocampus that is involved in spatial learning and memory, while the ventral hippocampus is more associated with limbic functions (Brooker, Gobeske, Chen, Peng, & Kessler, ; Hyer, Hunter, Katakam, Wolz, & Glasper, ; Kheirbek & Hen, ; Loxton & Canales, ; McHugh, Fillenz, Lowry, Rawlins, & Bannerman, ; Schoenfeld, McCausland, Sonti, & Cameron, ). Abnormalities in hippocampal function are associated with various neurological and psychiatric disorders in adults such as anxiety, schizophrenia and depression (Ampuero, Jury, Hartel, Marzolo, & Zundert, ; Brooker et al, ; Caruncho et al, ; Danzer, Kotloski, Walter, Hughes, & McNamara, ; Liu et al, ; Perez‐Domper et al, ; Yun et al, ).…”

“…Studies have demonstrated that decreased neurogenesis may be one cause of depression (Tamura et al, ). Indeed, many antidepressants have been shown to stimulate adult hippocampal neurogenesis (Brooker et al, ). It has been proposed that different sub‐regions of the hippocampus may regulate the distinct functions associated with the hippocampus (Bettio et al, ).…”

“…For example, the dorsal hippocampus appears to be involved in spatial learning and memory, while the ventral hippocampus is associated with stress, emotion and affect (Brooker et al, ; Hyer et al, ; Kheirbek & Hen, ; Loxton & Canales, ; McHugh et al, ; Schoenfeld et al, ). The hippocampus appears to have important functions in neurological and psychiatric disorders including anxiety, schizophrenia and depression (Ampuero et al, ; Brooker et al, ; Caruncho et al, ; Danzer et al, ; Liu et al, ; Perez‐Domper et al, ; Yun et al, ). Lesions in the ventral hippocampus and specifically ventral dentate gyrus lesions in rodents produce decreased anxiety‐like behaviour (Cameron & Glover, ).…”