Autism Spectrum Disorder (ASD) is caused by genetic, epigenetic, and environmental factors. Mutations in the human FMR1 gene, encoding the Fragile X Messenger Ribonucleoprotein 1 (FMRP), cause the most common monogenic form of ASD, the Fragile X Syndrome (FXS). This study explored the interaction between the FMR1 gene and a viral-like infection as an environmental insult, focusing on the impact on core autistic-like behaviors and the mGluR1/5-mTOR pathway. Pregnant heterozygous Fmr1 mouse females were exposed to maternal immune activation (MIA), by injecting the immunostimulant Poly (I:C) at the embryonic stage 12.5, simulating viral infections. Subsequently, ASD-like behaviors were analyzed in the adult offspring, at 8–10 weeks of age. MIA exposure in wild-type mice led to ASD-like behaviors in the adult offspring. These effects were specifically confined to the intrauterine infection, as immune activation at later stages, namely puberty (Pubertal Immune Activation, PIA) at post-natal day 35 or adulthood (Adult Immune Activation, AIA) at post-natal day 56, did not alter adult behavior. Importantly, combining the Fmr1 mutation with MIA exposure did not intensify core autistic-like behaviors, suggesting an occlusion effect. Mechanistically, MIA provided a strong activation of the mGluR1/5-mTOR pathway, leading to increased LTP and downregulation of FMRP specifically in the hippocampus. Finally, FMRP modulates mTOR activity via TSC2. These findings further strengthen the key role of the mGluR1/5-mTOR pathway in causing ASD-like core symptoms.

自闭症谱系障碍 （ASD） 是由遗传、表观遗传和环境因素引起的。编码脆性 X 信使核糖核蛋白 1 （FMRP） 的人类 FMR1 基因突变会导致最常见的单基因 ASD，即脆性 X 综合征 （FXS）。本研究探讨了 FMR1 基因与病毒样感染之间的相互作用作为环境伤害，重点关注对核心自闭症样行为和 mGluR1/5-mTOR 通路的影响。通过在胚胎期 12.5 注射免疫刺激剂 Poly （I：C），模拟病毒感染，将怀孕的杂合子 Fmr1 小鼠雌性暴露于母体免疫激活 （MIA）。随后，在 8-10 周龄的成年后代中分析了 ASD 样行为。野生型小鼠的 MIA 暴露导致成年后代出现 ASD 样行为。这些影响特别局限于宫内感染，因为后期的免疫激活，即出生后第 35 天的青春期（青春期免疫激活，PIA）或出生后第 56 天的成年期（成人免疫激活，AIA），并没有改变成人的行为。重要的是，将 Fmr1 突变与 MIA 暴露相结合并没有加剧核心自闭症样行为，这表明存在闭塞效应。从机制上讲，MIA 提供了 mGluR1/5-mTOR 通路的强烈激活，导致 LTP 增加和下调 FMRP，特别是在海马体中。最后，FMRP 通过 TSC2 调节 mTOR 活性。这些发现进一步加强了 mGluR1/5-mTOR 通路在引起 ASD 样核心症状中的关键作用。