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.

Keywords

autism spectrum disorder / microglia / myeloid cell trigger receptor 2 / retinoic acid receptor α / synaptic pruning

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