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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Stress induces behavioral disorders by promoting microglial phagocytosis via decreasing neuronal Dkk3
Xiao Chen1,2, Kaiqi Zhang1,2, Ye Li1,2
1School of Basic Medical Sciences, The second Hospital of Shandong University, Jinan, Shandong, 250012, China.
Abstract:
Microglia play an important role in the central nervous system, particularly with regard to altering synaptic function. However, the exact function of these microglia in major depressive disorder (MDD) remains unclear. Here, we report that in a chronic unpredictable mild stress (CUMS) model of depression, the expression of Dkk3 protein, the dickkopf Wnt signaling pathway inhibitor 3, was downregulated in the cornu ammonis 1 (CA1) region of the hippocampus. Neuronal-specific knockdown of Dkk3 increased microglial activation and engulfment, thereby contributing to depressive- and anxiety-like behaviors, via the Wnt-CX3CL1/CX3CR1 signaling pathway. With the ablation of microglia or chemical inhibition of CA1 pyramidal neurons, depressive-like behaviors were abolished. Moreover, treatment with a CX3CL1 McAb or XAV-939, an inhibitor of the Wnt pathway, ameliorated CUMS-induced behavioral deficits and decreased microglial phagocytosis of neuronal spines. Taken together, these results demonstrate that Dkk3 plays a critical role in regulating microglial engulfment, an effect which induces long-lasting disruptions of CA1 neurons in response to stress. These findings reveal important new mechanistic insights into the potential for Dkk3 to exert a protective role against MDD pathogenesis.
Insights
Downregulation of Dickkopf Wnt signaling pathway inhibitor 3 (Dkk3) in the hippocampus exacerbates depression and anxiety by activating microglia. Restoring Dkk3 function may offer a protective role against major depressive disorder (MDD).
Area of Science:
- Neuroscience
- Neuroimmunology
- Molecular Psychiatry
Background:
- Microglia are crucial for central nervous system function, including synaptic plasticity.
- The precise role of microglia in major depressive disorder (MDD) is not fully understood.
- Wnt signaling pathways are implicated in neuronal function and disease.
Purpose of the Study:
- To investigate the role of Dickkopf Wnt signaling pathway inhibitor 3 (Dkk3) in a chronic unpredictable mild stress (CUMS) model of depression.
- To elucidate the involvement of microglia and the Wnt-CX3CL1/CX3CR1 pathway in Dkk3-mediated depressive behaviors.
Main Methods:
- Utilized a CUMS rat model to mimic depression.
- Performed neuronal-specific knockdown of Dkk3.
- Assessed microglial activation, engulfment, and phagocytosis of neuronal spines.
- Employed microglia ablation and chemical inhibition of hippocampal neurons.
- Administered anti-CX3CL1 monoclonal antibody (McAb) and Wnt pathway inhibitor XAV-939.
Main Results:
- Dkk3 expression was downregulated in the CA1 region of the hippocampus in the CUMS model.
- Neuronal Dkk3 knockdown increased microglial activation and engulfment, leading to depressive- and anxiety-like behaviors.
- Ablation of microglia or inhibition of CA1 neurons abolished these behaviors.
- CX3CL1 McAb or XAV-939 treatment ameliorated behavioral deficits and reduced microglial phagocytosis.
Conclusions:
- Dkk3 critically regulates microglial engulfment, impacting CA1 neuronal integrity under stress.
- Dysregulation of the Dkk3-Wnt-CX3CL1/CX3CR1 axis contributes to MDD pathogenesis.
- Dkk3 may hold therapeutic potential for protecting against MDD.
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