The microglial innate immune receptor TREM2 participates in fear memory formation through excessive prelimbic
Le-le Zhang1,2,3, Peng Cheng1,2,3, Yuan-Qing Chu1,2,3
1National Medical Products Administration Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, China.
Introduction:
Fear memory formation has been implicated in fear- and stress-related psychiatric disorders, including post-traumatic stress disorder (PTSD) and phobias. Synapse deficiency and microglial activation are common among patients with PTSD, and induced in animal models of fear conditioning. Increasing studies now focus on explaining the specific mechanisms between microglia and synapse deficiency. Though newly-identified microglia regulator triggering receptor expressed on myeloid cells 2 (TREM2) plays a role in microglial phagocytic activity, its role in fear-formation remains unknown.
Methods:
We successfully constructed a fear- formation model by foot-shock. Four days after foot-shock, microglial capacity of synaptic pruning was investigated via western blotting, immunofluorescence and Golgi-Cox staining. Prelimbic chemical deletion or microglia inhibition was performed to detect the role of microglia in synaptic loss and neuron activity. Finally, Trem2 knockout mice or wild-type mice with Trem2 siRNA injection were exposed to foot-shock to identify the involvement of TREM2 in fear memory formation.
Results:
The results herein indicate that the foot-shock protocol in male mice resulted in a fear formation model. Mechanistically, fear conditioning enhanced the microglial capacity for engulfing synapse materials, and led to glutamatergic neuron activation in the prelimbic cortex. Prelimbic chemical deletion or microglia inhibition improved fear memory formation. Further investigation demonstrated that TREM2 regulates microglial phagocytosis, enhancing synaptic pruning. Trem2 knockout mice showed remarkable reductions in prelimbic synaptic pruning and reduced neuron activation, with decreased fear memory formation.
Discussion:
Our cumulative results suggest that prelimbic TREM2-mediated excessive microglial synaptic pruning is involved in the fear memory formation process, leading to development of abnormal stress-related behavior.
Insights
Excessive microglial pruning of synapses, regulated by TREM2 (triggering receptor expressed on myeloid cells 2), contributes to fear memory formation and stress-related disorders.
Area of Science:
- Neuroscience
- Cell Biology
- Psychiatry
Background:
- Fear memory formation is linked to stress-related disorders like PTSD.
- Microglial activation and synapse deficiency are observed in PTSD.
- The role of TREM2 (triggering receptor expressed on myeloid cells 2) in fear memory is unclear.
Purpose of the Study:
- To investigate the role of microglia and TREM2 in fear memory formation.
- To understand the mechanisms linking microglial activity, synaptic pruning, and fear memory.
Main Methods:
- A fear memory model was established using foot-shock in male mice.
- Microglial synaptic pruning capacity was assessed using western blotting, immunofluorescence, and Golgi-Cox staining.
- The involvement of TREM2 was examined in Trem2 knockout mice and via siRNA injection.
Main Results:
- Foot-shock induced fear memory, increased microglial engulfment of synapses, and activated prelimbic glutamatergic neurons.
- Inhibiting microglia or deleting TREM2 reduced synaptic pruning and fear memory.
- TREM2 (triggering receptor expressed on myeloid cells 2) was found to regulate microglial phagocytosis and synaptic pruning.
Conclusions:
- Excessive TREM2-mediated microglial synaptic pruning in the prelimbic cortex is implicated in fear memory formation.
- This process may contribute to abnormal stress-related behaviors and psychiatric disorders.
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