Retinoic acid administration normalizes aberrant microglial activation via regulating TREM2 transcription in the PFC of valproic acid induced autism rat
Retinoic acid administration normalizes aberrant microglial activation via regulating TREM2 transcription in the PFC of valproic acid induced autism rat
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DOI：
10.1016/j.neulet.2023.137193
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发表时间：
2023-03
影响因子：
2.5
通讯作者：
Lijuan Luo;Tingyu Li;Qionghui Wu;B. Yuan;Chaoqun Hu;Ting Yang;Hua Wei;Jie Chen
中科院分区：
文献类型：
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作者：
Lijuan Luo;Tingyu Li;Qionghui Wu;B. Yuan;Chaoqun Hu;Ting Yang;Hua Wei;Jie Chen
自闭症谱系障碍(ASD)是一种复杂的神经发育疾病，其发病机制尚不清楚。视黄酸-视黄酸受体α(RAR-α)信号转导中断和小胶质细胞异常激活被认为参与了ASD的发病过程。然而，RA-RARα信号对ASD小胶质细胞激活的影响及其机制尚不清楚。在此，我们发现，在丙戊酸诱导的自闭症大鼠中，RA-RARα信号转导受到抑制，小胶质细胞活化增加。此外，我们给VPA大鼠服用RA，发现RA改善了VPA大鼠的孤独症样行为，抑制了小胶质细胞的激活，并使小胶质细胞极化正常化。此外，RA组大鼠的前额叶皮质RARα和TREM2的表达水平也明显升高。染色质免疫沉淀(ChIP)和双荧光素酶报告实验证实，RARα可以通过与启动子结合来调节TREM2基因的转录活性。结论：维甲酸可通过抑制小胶质细胞活化，并通过RARα调控TREM2转录而使小胶质细胞极化正常化，从而改善孤独症大鼠的行为。
Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with an unclear underlying pathogenesis. Disruption of retinoic acid (RA)-retinoic acid receptor α (RARα) signaling and aberrant microglial activation were reported to be involved in the pathogenesis of ASD. However, the effect of RA-RARα signaling on microglial activation in ASD and the underlying mechanisms are unknown. Herein, we found inhibited RA-RARα 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 activation and normalized microglial polarization in VPA rats. Additionally, the expression levels of RARα 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 RARα 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 RARα.