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TREM2 Downregulation Disrupts Microglial Function and Synaptic Pruning Through RA/RARα Signaling: Mechanisms
Min Lu1,2,3, Kexin Bai1,2,3, Yali Bai1,2,3
1Growth, Development and Mental Health Center of Children and Adolescents Children's Hospital of Chongqing Medical University Chongqing China.
Abstract:
Autism spectrum disorder (ASD) involves neuroimmune dysregulation and synaptic pruning defects. This study aimed to investigate the role of triggering receptor expressed on myeloid cells 2 (TREM2) in ASD pathogenesis and its link to retinoic acid (RA)/retinoic acid receptor α (RARα) signaling. Prefrontal cortex-specific knockdown of TREM2 in rats induced core ASD-like behaviors (e.g., social deficits), microglial hyperactivation, aberrant synaptic pruning, reduced serum soluble TREM2 (sTREM2) levels, and disrupted RA/RARα signaling. Oral RA supplementation (6 mg/[kg·day]) reversed these neuroimmune abnormalities and behavioral impairments. In vitro studies demonstrated that TREM2 knockdown and RA supplementation induced RARα-level alterations consistent with in vivo observations. These findings indicated that TREM2 deficiency was a key factor in the pathophysiology of ASD, mediated by the RA/RARα signaling pathway. Furthermore, serum sTREM2 might serve as a potential diagnostic biomarker for ASD. Collectively, these findings underscore the pivotal role of TREM2 in ASD pathogenesis and provide novel perspectives for diagnostic and therapeutic strategies.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency causes autism spectrum disorder (ASD)-like behaviors by disrupting retinoic acid signaling. Supplementation with retinoic acid (RA) reversed these effects, suggesting TREM2
Area of Science:
- Neuroimmunology
- Neurodevelopmental Disorders
- Molecular Psychiatry
Background:
- Autism spectrum disorder (ASD) is characterized by neuroimmune dysregulation and synaptic pruning abnormalities.
- The role of triggering receptor expressed on myeloid cells 2 (TREM2) in ASD pathogenesis remains unclear.
- Retinoic acid (RA) and its receptor alpha (RARα) signaling pathway are implicated in neurodevelopment.
Purpose of the Study:
- To investigate the role of TREM2 in ASD pathogenesis.
- To explore the link between TREM2 and RA/RARα signaling in ASD.
- To identify potential diagnostic biomarkers for ASD.
Main Methods:
- Prefrontal cortex-specific TREM2 knockdown in rats to induce ASD-like phenotypes.
- Assessment of behavioral deficits, microglial activation, synaptic pruning, and serum soluble TREM2 (sTREM2) levels.
- In vitro studies to examine the effects of TREM2 knockdown and RA supplementation on RARα levels.
Main Results:
- TREM2 knockdown induced ASD-like behaviors, microglial hyperactivation, aberrant synaptic pruning, and disrupted RA/RARα signaling.
- Reduced serum sTREM2 levels were observed in rats with TREM2 knockdown.
- Oral RA supplementation reversed the observed neuroimmune abnormalities and behavioral impairments.
Conclusions:
- TREM2 deficiency is a key factor in ASD pathophysiology, mediated by the RA/RARα signaling pathway.
- Serum sTREM2 may serve as a potential diagnostic biomarker for ASD.
- Targeting TREM2 and RA/RARα signaling offers novel therapeutic strategies for ASD.
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