Microglial CR3-mediated synaptic pruning in the dmPFC promotes the generation and maintenance of chronic muscle pain
Meiling Luo1, Likai Wang1, Yanan Liang1
1Rehabilitation Center, Qilu Hospital of Shandong University, Jinan, China.
Abstract:
Chronic muscle pain (CMP) is highly prevalent, frequently comorbid with emotional disorders and characterized by a high risk of recurrence. Yet, the complex mechanisms underlying the generation and maintenance of CMP remain unclear, limiting the development of therapy. Here we identified suppressed glutamatergic neuronal excitability and reduced synaptic plasticity in the dorsomedial prefrontal cortex (dmPFC) of CMP rats using fiber photometry, patch-clamp, in vivo recording of field potentials and other techniques. The optochemical genetical activation of dmPFC glutamatergic neurons alleviated pain and anxiety-like behaviors. Single-cell RNA sequencing revealed a marked upregulation of proinflammatory microglia and complement receptor 3 (CR3) in the dmPFC, which correlated with reduced neuronal excitability and synaptic function. Flow cytometry and immunofluorescence further showed that hyperactive glutamatergic neurons induced microglial activation, proliferation, polarization and chemotaxis. Notably, the inhibition of microglia or knockdown of microglial CR3 restored dmPFC glutamatergic neuronal excitability and synaptic plasticity, thereby alleviating hyperalgesia and anxiety-like behaviors. This study demonstrates that microglial CR3-dependent synaptic pruning underlies suppressed glutamatergic neuronal excitability and reduced synaptic plasticity, playing a pivotal role in CMP generation and maintenance. These findings uncover novel microglia-neuron interactions and offer promising therapeutic targets for CMP and its emotional comorbid disorders. Microglial CR3-mediated synaptic pruning in the dmPFC suppresses glutamatergic neuronal excitability, contributing to chronic muscle pain generation and maintenance and represents a promising therapeutic target.
Insights
Microglia-mediated synaptic pruning in the brain
Area of Science:
- Neuroscience
- Immunology
- Pain Research
Background:
- Chronic muscle pain (CMP) is common, often linked with emotional disorders, and tends to recur.
- The underlying mechanisms of CMP are not fully understood, hindering effective treatment development.
Purpose of the Study:
- To investigate the neural mechanisms of CMP generation and maintenance.
- To explore the role of microglia and synaptic plasticity in CMP.
Main Methods:
- Utilized techniques including fiber photometry, patch-clamp, in vivo field potential recording, single-cell RNA sequencing, flow cytometry, and immunofluorescence in CMP rat models.
- Investigated the function of glutamatergic neurons in the dorsomedial prefrontal cortex (dmPFC) and microglial activity.
Main Results:
- Identified suppressed glutamatergic neuronal excitability and reduced synaptic plasticity in the dmPFC of CMP rats.
- Found increased proinflammatory microglia expressing complement receptor 3 (CR3) in the dmPFC, correlating with impaired neuronal function.
- Demonstrated that inhibiting microglia or microglial CR3 restored neuronal function and alleviated pain and anxiety behaviors.
Conclusions:
- Microglial CR3-dependent synaptic pruning suppresses glutamatergic neuronal excitability in the dmPFC, contributing to CMP.
- Novel microglia-neuron interactions are identified, highlighting microglial CR3 as a potential therapeutic target for CMP and associated emotional disorders.
