Microglial transglutaminase 2 deficiency causes impaired synaptic remodelling and cognitive deficits in mice
Cong Liu1,2,3, Xing Gao1,4, Ruo-Xi Shi1,4
1State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Abstract:
Microglia are the primary source of transglutaminase 2 (TGM2) in the brain; however, the roles of microglial TGM2 in neural development and disease are still not well known. The aim of this study is to elucidate the role and mechanisms of microglial TGM2 in the brain. A mouse line with a specific knockout of Tgm2 in microglia was generated. Immunohistochemistry, Western blot and qRT-PCR assays were performed to evaluate the expression levels of TGM2, PSD-95 and CD68. Confocal imaging, immunofluorescence staining and behavioural analyses were conducted to identify phenotypes of microglial TGM2 deficiency. Finally, RNA sequencing, qRT-PCR and co-culture of neurons and microglia were used to explore the potential mechanisms. Deletion of microglial Tgm2 causes impaired synaptic pruning, reduced anxiety and increased cognitive deficits in mice. At the molecular level, the phagocytic genes, such as Cq1a, C1qb and Tim4, are significantly down-regulated in TGM2-deficient microglia. This study elucidates a novel role of microglial TGM2 in regulating synaptic remodelling and cognitive function, indicating that microglia Tgm2 is essential for proper neural development.
Insights
Microglial transglutaminase 2 (TGM2) is crucial for synaptic pruning and cognitive function. Its absence impairs neural development by down-regulating phagocytic genes in microglia.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia are the brain's primary source of transglutaminase 2 (TGM2).
- The specific functions of microglial TGM2 in neural development and disease remain largely unknown.
- Understanding these roles is critical for neurodevelopmental and neurodegenerative research.
Purpose of the Study:
- To investigate the role and underlying mechanisms of microglial TGM2 in the brain.
- To determine the impact of TGM2 deficiency in microglia on neural development and function.
- To identify molecular pathways regulated by microglial TGM2.
Main Methods:
- Generation of a mouse model with Tgm2 specifically knocked out in microglia.
- Utilized immunohistochemistry, Western blot, and qRT-PCR to assess TGM2 and synaptic marker expression.
- Employed confocal imaging, immunofluorescence, behavioral analyses, and RNA sequencing to evaluate functional and molecular changes.
Main Results:
- Microglial TGM2 deficiency led to impaired synaptic pruning and increased cognitive deficits.
- Mice lacking microglial TGM2 exhibited reduced anxiety-like behaviors.
- Key phagocytic genes (e.g., Cq1a, C1qb, Tim4) were significantly downregulated in TGM2-deficient microglia.
Conclusions:
- Microglial TGM2 plays a novel and essential role in regulating synaptic remodeling during neural development.
- TGM2 in microglia is vital for maintaining proper cognitive function and synaptic integrity.
- These findings highlight microglial TGM2 as a potential therapeutic target for neurological disorders.
