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Depletion of HSP60 in Microglia Leads to Synaptic Dysfunction and Depression-Like Behaviors Through Enhanced Synaptic
Wenhui Zhu1, Jinlong Chang2, Liusuyan Tian3
1Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single-Cell and Extracellular Vesicles, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Aims:
Microglia, as resident macrophages in the brain, play an important role in depression. Heat shock protein 60 (HSP60), as a chaperone protein, plays a role in cell stress. However, the role of microglial HSP60 in depression remains unclear.
Methods:
CX3CR1-CreER was used to generate microglial-specific HSP60 knockout (HSP60 cKO) mice. Behavioral tests, western blotting, Golgi staining, biochemical assays, and proteomics were employed to assess depression-like symptoms, microglial activation, and synaptic changes.
Results:
HSP60 cKO male mice exhibited depressive-like behaviors, without anxiety-like behavior, including increased immobility in the forced swimming and tail suspension tests, reduced sucrose preference, and elevated corticosterone (CORT) levels, indicating HPA axis activation. Microglial activation was confirmed by the increased expression levels of CD68 and CD86, the elevated transcription of the cybb gene, and reduced branch complexity. Enhanced phagocytosis of excitatory synapses, reduced dendritic spine density, and decreased glutamate levels were observed, with downregulation of synaptic proteins (AMPAR2, Synapsin-1, PSD95), indicating dysregulated synaptic pruning. Moreover, GO analysis showed 20 significant differentially expressed proteins (DEPs) from proteomics are associated with the presynaptic endosome, which plays a crucial role in maintaining synaptic function. Treatment with PLX3397, a CSF1R inhibitor, alleviated depressive-like behaviors and restored synaptic density in HSP60 cKO male mice.
Conclusions:
HSP60 deletion in microglia leads to overactivation of microglia, impaired synaptic function, and depression-like behaviors, highlighting the importance of microglial homeostasis in mood regulation and the potential therapeutic role of microglial modulation.
Insights
Deleting heat shock protein 60 (HSP60) in microglia causes depression-like behaviors and synaptic dysfunction. Modulating microglial activity may offer new depression therapies.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia, the brain's resident immune cells, are implicated in depression.
- Heat shock protein 60 (HSP60) is involved in cellular stress responses.
- The specific role of microglial HSP60 in depression remains largely unknown.
Purpose of the Study:
- To investigate the function of microglial HSP60 in the context of depression.
- To elucidate the molecular mechanisms linking microglial HSP60 to depression-like behaviors and synaptic integrity.
Main Methods:
- Generated microglial-specific HSP60 knockout (HSP60 cKO) mice using CX3CR1-CreER technology.
- Assessed depression-like and anxiety-like behaviors through various behavioral tests.
- Analyzed microglial activation, synaptic changes, and protein expression using western blotting, Golgi staining, biochemical assays, and proteomics.
Main Results:
- HSP60 cKO male mice displayed depression-like behaviors, including increased immobility and reduced sucrose preference, alongside elevated corticosterone levels.
- Microglial activation was evident, characterized by increased CD68/CD86 expression and reduced complexity.
- Synaptic function was impaired, with enhanced phagocytosis of excitatory synapses, reduced dendritic spine density, and altered glutamate levels, suggesting dysregulated synaptic pruning.
- Proteomics identified presynaptic endosome-associated proteins crucial for synaptic function.
- Treatment with a CSF1R inhibitor (PLX3397) ameliorated depressive behaviors and restored synaptic density.
Conclusions:
- Microglial HSP60 deletion triggers microglial overactivation, leading to synaptic dysfunction and depression-like behaviors.
- Maintaining microglial homeostasis is critical for mood regulation.
- Targeting microglial pathways presents a potential therapeutic strategy for depression.
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