TREM2 Downregulation Disrupts Microglial Function and Synaptic Pruning Through RA/RARα Signaling: Mechanisms...

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.