TREM2 Downregulation Disrupts Microglial Function and Synaptic Pruning Through RA/RARα Signaling: Mechanisms Underlying Autism‐Like Behaviors

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.