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Updated: Sep 14, 2025
Author Spotlight: In Vitro Co-Culture Model for Studying Microglia-Neuronal Interactions in Disease Conditions
Published on: July 26, 2024
Microglia-neuronal communication mediated by P2X4R-BDNF-TrkB promotes synaptic plasticity and anterior cingulate
Yanan Liang1, Meiling Luo2, Qianxi Xu2
1Rehabilitation Center, Qilu Hospital of Shandong University, Jinan, Shandong, China; University of Health and Rehabilitation Sciences, Qingdao, Shandong, China.
Background:
Microglia-neuronal communication is crucial for the development and maintenance of pain. However, the exact mechanisms underlying this interaction and its role in anterior cingulate cortex (ACC) circuitry in pain regulation are under exploration.
Methods:
We explored the role of P2X4R-brain-derived neurotrophic factor (BDNF)-TrkB signalling of ACC in regulating muscle pain (MP). Mechanical and thermal pain thresholds along with open field tests were used to assess pain and anxiety-like behaviours. Golgi staining, transmission electron microscopy, and patch-clamp recordings were performed to evaluate synaptic plasticity changes. Meanwhile, cFos staining and calcium imaging substantiate the neuronal excitability. In addition, we used chemogenetic and optogenetic approaches to manipulate ACC neuronal activity.
Results:
The ACC exhibited increased excitability, together with enhanced synaptic plasticity in rats with chronic MP. Microglial inhibition alleviated pain and anxiety-like behaviours. Furthermore, microglial P2X4R promoted BDNF expression, which acted on TrkB to regulate neuronal excitability and synaptic plasticity in ACC; these effects were reversed by P2X4R knockdown and TrkB inhibition in MP. Chemogenetic and optogenetic suppression of ACC hyperactivity relieved chronic MP and anxiety-like behaviours.
Conclusions:
Our findings highlight a critical microglia-neuronal communication via the P2X4R-BDNF-TrkB signalling, which enhances synaptic plasticity and cortical excitability in the anterior cingulate cortex, thereby participating in the regulation of muscle pain. Understanding how to assess and modulate microglia-neuronal communication and abnormal cortical activity will be key to developing novel therapies for MP disorders.
Insights
Microglia communicate with neurons via P2X4R-BDNF-TrkB signaling in the anterior cingulate cortex, enhancing synaptic plasticity and regulating muscle pain. Modulating this pathway offers potential therapies for pain disorders.
Area of Science:
- Neuroscience
- Pain Research
- Cellular Communication
Background:
- Microglia-neuronal communication is vital for pain development and maintenance.
- The anterior cingulate cortex (ACC) plays a role in pain regulation, but mechanisms are under investigation.
Purpose of the Study:
- To explore the role of P2X4R-brain-derived neurotrophic factor (BDNF)-TrkB signaling in the ACC for muscle pain (MP) regulation.
- To investigate the impact of this signaling pathway on synaptic plasticity and neuronal excitability in the ACC during chronic MP.
Main Methods:
- Assessed pain and anxiety behaviors using behavioral tests.
- Evaluated synaptic plasticity via Golgi staining, electron microscopy, and patch-clamp recordings.
- Measured neuronal excitability using cFos staining and calcium imaging.
- Manipulated ACC neuronal activity using chemogenetics and optogenetics.
Main Results:
- Chronic MP increased ACC excitability and synaptic plasticity in rats.
- Microglial inhibition reduced pain and anxiety behaviors.
- Microglial P2X4R promoted BDNF expression, enhancing TrkB-mediated neuronal excitability and plasticity, effects reversed by P2X4R knockdown or TrkB inhibition.
- Suppression of ACC hyperactivity alleviated chronic MP and anxiety behaviors.
Conclusions:
- Microglia-neuronal communication via P2X4R-BDNF-TrkB signaling in the ACC is critical for muscle pain regulation.
- This pathway enhances synaptic plasticity and cortical excitability, contributing to MP.
- Targeting microglia-neuronal communication and abnormal cortical activity may lead to novel MP therapies.
