Retinoic acid administration normalizes aberrant microglial activation via regulating TREM2 transcription in the PFC of valproic acid induced autism rat

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with an unclear underlying patho-genesis. Disruption of retinoic acid (RA)-retinoic acid receptor alpha (RAR alpha) signaling and aberrant microglial activation were reported to be involved in the pathogenesis of ASD. However, the effect of RA-RAR alpha signaling on microglial activation in ASD and the underlying mechanisms are unknown. Herein, we found inhibited RA-RAR alpha signaling and increased microglial activation in valproic acid (VPA)-induced autism rats. Furthermore, we administered RA to VPA rats and found that RA ameliorated autism-like behaviors, inhibited microglial acti-vation and normalized microglial polarization in VPA rats. Additionally, the expression levels of RAR alpha and triggering receptor expressed on myeloid cells 2 (TREM2) were increased in the prefrontal cortex (PFC) of VPA rats given RA. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays confirmed that RAR alpha can regulate the transcriptional activity of the TREM2 gene by binding to its promoter. We conclude that RA administration ameliorates autism-like behaviors in VPA rats by inhibiting microglial activation and normalizing microglial polarization through the regulation of TREM2 transcription by RAR alpha.