Qiao Sheng-Nan, Wang Sung Eun, Kim Kun-Yong, Jo Sungsin, Jiang Yong-Hui
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Department of Biology, Soonchunhyang University, Soonchunhyang-ro 22, Sinchangmyeon, Asan, South Korea.
bioRxiv. 2025 Aug 11:2025.08.07.669241. doi: 10.1101/2025.08.07.669241.
Behavioral regression occurs in ~40% of -associated autism spectrum disorder (ASD). We previously reported that significant behavioral regression in a small cohort with haploinsufficiency patients, triggered by subclinical infections, responded to immunomodulator treatments. We hypothesize that behavioral regression results from the interplay between deficiency and neuroinflammation. Using exon 4-22 deletion heterozygous mutant ( ) mouse, which shows no significant behavior impairments, we established a preclinical model - haploinsufficiency mouse undergoing systemic inflammation challenge via intraperitoneal injection of lipopolysaccharides (LPS). We found that, two weeks after LPS challenge, wild-type mice (WT) recovered but mice exhibited motor impairment, anxiety-like behaviors, and excessive grooming, similar to exon 4-22 deletion homozygous mutants. Anti-inflammatory treatment partially reversed LPS-induced behavioral changes. Transcriptomic analysis revealed upregulation of neuroinflammation-related genes and downregulation of synaptic function-related genes in mice in response to LPS. Especially, pro-inflammatory genes and microglia markers were overly activated that may result from the increased Toll-Like Receptor 4 (TLR4) expression in microglia in mice. Our findings indicate that neuroinflammation increases the penetrance of behavioral impairment in haploinsufficiency mice and support a potential mechanism for the behavioral regression in human disorders for future investigations.
行为倒退发生在约40%的[相关内容缺失]自闭症谱系障碍（ASD）中。我们之前报道过，在一小群[相关内容缺失]单倍剂量不足患者中，由亚临床感染引发的显著行为倒退对免疫调节剂治疗有反应。我们假设行为倒退是由[相关内容缺失]缺陷与神经炎症之间的相互作用导致的。使用外显子4 - 22缺失杂合突变（[相关内容缺失]）小鼠，其未表现出明显行为缺陷，我们建立了一个临床前模型——通过腹腔注射脂多糖（LPS）使[相关内容缺失]单倍剂量不足小鼠接受全身炎症挑战。我们发现，在LPS挑战两周后，野生型小鼠（WT）恢复了，但[相关内容缺失]小鼠表现出运动障碍、焦虑样行为和过度梳理行为，类似于外显子4 - 22缺失纯合突变体。抗炎治疗部分逆转了LPS诱导的行为变化。转录组分析显示，[相关内容缺失]小鼠在LPS刺激下神经炎症相关基因上调，突触功能相关基因下调。特别是，促炎基因和小胶质细胞标志物过度激活，这可能是由于[相关内容缺失]小鼠小胶质细胞中Toll样受体4（TLR4）表达增加所致。我们的研究结果表明，神经炎症增加了[相关内容缺失]单倍剂量不足小鼠行为障碍的发生率，并为人类[相关疾病缺失]行为倒退的潜在机制提供了支持，以供未来研究。
