Key Laboratory of Ethnomedicine of Ministry of Education, Center on Translational Neuroscience, School of Pharmacy, Minzu University of China, Beijing, China.
NHC Key Laboratory of Birth Defects Research, Prevention and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China.
Pharmacol Res. 2023 Nov;197:106965. doi: 10.1016/j.phrs.2023.106965. Epub 2023 Oct 17.
The development and progression of autism spectrum disorder (ASD) is characterized by multiple complex molecular events, highlighting the importance of the prefrontal brain regions in this process. Exosomes are nanovesicles that play a critical role in intercellular communication. Peripheral systems influence brain function under both physiological and pathological conditions. We investigated whether this influence was mediated by the direct sensing of peripheral blood exosomes by brain cells. Administration of serum exosomes from rats with valproic acid-induced ASD resulted in ASD-related phenotypes in mice, whereas exosomes from normal rats did not exhibit such effects. RNA sequencing and bioinformatics analysis suggested that negative regulation of medial prefrontal cortex (mPFC) insulin-like growth factor 1 (IGF-1) by exosome-derived miR-29b-3p may contribute to these ASD-associated effects. Further evidence showed that miR-29b-3p-enriched exosomes crossed the blood-brain barrier to reach the mPFC, subsequently inducing the suppression of IGF-1 expression in neurons. Optogenetic activation of excitatory neurons in the mPFC improved behavioral abnormalities in exosome-treated mice. The addition of exogenous IGF-1 or inhibition of miR-29b-3p expression in the mPFC also rescued the ASD-related phenotypes in mice. Importantly, administration of miR-29b-3p-enriched serum exosomes from human donors with ASD into the mouse medial prefrontal cortex was sufficient to induce hallmark ASD behaviors. Together, our findings indicate that blood-brain cross-talk is crucial for ASD pathophysiology and that the brain may sense peripheral system changes through exosomes, which could serve as the basis for future neurological therapies.
自闭症谱系障碍 (ASD) 的发展和进展以多种复杂的分子事件为特征，突出了前额叶脑区在这一过程中的重要性。外泌体是在细胞间通讯中起关键作用的纳米囊泡。外周系统在生理和病理条件下影响大脑功能。我们研究了这种影响是否通过脑细胞直接感知外周血外泌体来介导。给予丙戊酸诱导 ASD 的大鼠血清外泌体可导致小鼠出现 ASD 相关表型，而正常大鼠的外泌体则没有这种作用。RNA 测序和生物信息学分析表明，外泌体衍生的 miR-29b-3p 对内侧前额叶皮层 (mPFC) 胰岛素样生长因子 1 (IGF-1) 的负调控可能导致这些与 ASD 相关的效应。进一步的证据表明，富含 miR-29b-3p 的外泌体穿过血脑屏障到达 mPFC，随后诱导神经元中 IGF-1 表达的抑制。mPFC 中兴奋性神经元的光遗传学激活改善了外泌体处理小鼠的行为异常。在 mPFC 中添加外源性 IGF-1 或抑制 miR-29b-3p 的表达也挽救了小鼠的 ASD 相关表型。重要的是，将来自 ASD 人类供体的富含 miR-29b-3p 的血清外泌体给予小鼠内侧前额叶皮层足以诱导 ASD 的标志性行为。总之，我们的研究结果表明，血脑交叉对话对于 ASD 的病理生理学至关重要，大脑可能通过外泌体感知外周系统的变化，这可能为未来的神经治疗提供基础。
