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Hippocampal BMP signaling as a common pathway for antidepressant action.

ABSTRACT: The benefits of current treatments for depression are limited by low response rates, delayed therapeutic effects, and multiple side effects. Antidepressants affect a variety of neurotransmitter systems in different areas of the brain, and the mechanisms underlying their convergent effects on behavior have been unclear. Here we identify hippocampal bone morphogenetic protein (BMP) signaling as a common downstream pathway that mediates the behavioral effects of five different antidepressant classes (fluoxetine, bupropion, duloxetine, vilazodone, trazodone) and of electroconvulsive therapy. All of these therapies decrease BMP signaling and enhance neurogenesis in the hippocampus. Preventing the decrease in BMP signaling blocks the effect of antidepressant treatment on behavioral phenotypes. Further, inhibition of BMP signaling in hippocampal newborn neurons is sufficient to produce an antidepressant effect, while chemogenetic silencing of newborn neurons prevents the antidepressant effect. Thus, inhibition of hippocampal BMP signaling is both necessary and sufficient to mediate the effects of multiple classes of antidepressants.

SUBMITTER: Tunc-Ozcan E

PROVIDER: S-EPMC8740160 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Hippocampal BMP signaling as a common pathway for antidepressant action.

Tunc-Ozcan Elif E Brooker Sarah M SM Bonds Jacqueline A JA Tsai Yung-Hsu YH Rawat Radhika R McGuire Tammy L TL Peng Chian-Yu CY Kessler John A JA

Cellular and molecular life sciences : CMLS 20211222 1

The benefits of current treatments for depression are limited by low response rates, delayed therapeutic effects, and multiple side effects. Antidepressants affect a variety of neurotransmitter systems in different areas of the brain, and the mechanisms underlying their convergent effects on behavior have been unclear. Here we identify hippocampal bone morphogenetic protein (BMP) signaling as a common downstream pathway that mediates the behavioral effects of five different antidepressant classe ...[more]

PMID: 34936033

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Project description:The dentate gyrus (DG) of the hippocampus is one of major targets for antidepressant treatments. Our recent research has revealed that selective serotonin reuptake inhibitor (SSRI) treatment causes a long-lasting change in the phenotypes of mature dentate granule neurons to immature state in adult mouse DG. However, it is unknown whether this M-bM-^@M-^\dematurationM-bM-^@M-^] of DG is a common effect of antidepressant treatments and what mechanisms underlie it. Using electroconvulsive stimulation (ECS), a model of highly effective and fast-acting antidepressant therapy, here we show that neural stimulation via ECS induces rapid and lasting dematuration of granule neurons in DG. A single or few times of stimulation transiently reduced mature marker expression and mature synaptic functions. Repetitive stimulation converted this transient dematuration into a stable form lasting more than 1 month. Dematured granule neurons showed higher excitability, and an increase in GABA-mediated inhibition by the benzodiazepine diazepam prevented the lasting maintenance phase of dematuration without affecting the initial induction phase. Our study suggests that dematuration of DG is a common cellular mechanism underlying effects of different types of antidepressant treatments, and demonstrate a novel role for excitation/inhibition balance in bidirectional regulation of the state of neuronal maturation in the adult brain. Mice were decapitated after the 11 times of ECS (or Sham) or 4 weeks treatment of fluoxetine (or vehicle) at a dose of 22 mg/kg. The brains were sliced and the frequency facilitation of mossy fiber synapse was measured in each sample. The samples which exhibited low frequency facilitation were selected to be used as dematured DG (n = 3) and the dentate gyrus was dissected from each sample. Total RNA was extracted by using an RNeasy micro kit (Qiagen) and the samples of the same groups were put together. From each group, 100 ng of total RNA was amplified with 3M-bM-^@M-^YIVT Express kit (Affymetrix, Inc., Santa Clara, CA, USA). All samples were hybridized to the GeneChip mouse genome 430A 2.0 array (Affymetrix, Inc.), and the microarray suite 5.0 of the Affymetrix gene chip operating software was used for the analysis of the GeneChip data.

Project description:IntroductionAdult hippocampal neurogenesis (AHN) is acknowledged to play a critical role in depression. Emerging evidence suggests that the Wnt/β-catenin pathway can modulate hippocampal neurogenesis. Crocin, a natural carotenoid, possesses antidepressant property. Yet, how it affects neurogenesis and exerts antidepressant response remains unknown.ObjectiveTo explore the role of AHN and Wnt/β-catenin in the antidepressant action of crocin.MethodsDepressive-related behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and sexual behaviors were performed following crocin treatment. Neurogenesis was characterized via immunohistochemistry, immunofluorescence, Golgi staining and electrophysiology approach. Wnt/β-catenin signaling was examined with western blot analysis. The role of AHN Wnt/β-catenin cascade in crocin's antidepressant response was assessed by conditional removal of glial fibrillary acidic protein (GFAP)-expressing newborn neural cells, temozolomide administration, microinfusion of Dkk1 or viral-mediated shRNA of Wnt3a.ResultsCrocin decreased the immobility duration in TST and FST without impairing the performance in sexual behaviors. Crocin boosted the proliferation and differentiation of progenitors, and promoted dendritic maturation and functional integration of hippocampal newborn neurons. Conditional removal of GFAP-expressing neural cells or temozolomide administration impaired the antidepressant response of crocin. Additionally, Wnt/β-catenin signaling was promoted following crocin treatment. In chronic unpredictable mild stress (CUMS) murine model, crocin treatment displayed antidepressant response in SPT, FST and TST, and restored the neurogenesis levels and Wnt/β-catenin signaling impaired by CUMS. Infusion of Dickkopf-1 (DKK1) or knockdown of Wnt3a in the hippocampus impaired the antidepressant response of crocin.ConclusionCrocin exerted antidepressant response, which was dependent on enhancement of AHN and activation of the Wnt/β-catenin pathway.

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Hippocampal BMP signaling as a common pathway for antidepressant action.

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Hippocampal BMP signaling as a common pathway for antidepressant action.

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