Jiang Junhong, Zhang Ling, Wu De, Zhao Dongjun, Ying Songcheng, Ding Shenggang
Department of Pediatrics, The first Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China; Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, PR China; Beijing Children's Hospital, Capital Medical University, China National Clinical Research Center of Respiratory Diseases, Beijing, PR China.
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, PR China.
Brain Res Bull. 2025 Jan;220:111154. doi: 10.1016/j.brainresbull.2024.111154. Epub 2024 Nov 30.
Autism spectrum disorders (ASD) are characterized by social skill deficits and behavior impairments. Exposure to valproic acid (VPA) has been linked to ASD in humans and ASD-like behaviors in rodents. Clinical evidence suggests that immunological damage can worsen ASD symptoms in humans.
This study aimed to investigate the potential of lipopolysaccharide (LPS) to induce neuroinflammation in a VPA-induced autism male model.
and methods: Pregnant Sprague Dawley rats were injected with 500 mg/kg of VPA on gestational day 12.5 to create an ASD rat model in their offspring. Male offspring from VPA-injected group received 10 mg/kg of LPS on postnatal day 20. Immunohistochemistry, western blotting, and immunofluorescence were used to assess the expression of NF-κB signaling pathway-related proteins and microglia in the prefrontal cortex and hippocampus. Gene Ontology and pathway enrichment analyses were conducted to predict the function of key synaptic proteins, which were further validated through real-time polymerase chain reaction analysis.
The results showed that VPA exposure led to increased locomotor activity, social impairment, and repetitive behaviors in male rats. NF-κB signaling pathway-related proteins were upregulated, and microglial numbers were elevated in the VPA-induced group. Furthermore, synaptic dysfunction was observed in the brains of offspring exposed to VPA. Importantly, LPS administration exacerbated autism-related behaviors in VPA-exposed male rats by promoting NF-κB signaling pathway activation, increasing microglial numbers, and downregulating key synaptic proteins.
This study not only contributed to understanding the importance of the NF-κB signaling pathway, microglia, and synaptic proteins in the progression of ASD, but also identified that LPS induces neuroinflammation in a valproic acid-induced male model of autism.
自闭症谱系障碍（ASD）的特征是社交技能缺陷和行为障碍。人类接触丙戊酸（VPA）与ASD有关，在啮齿动物中与ASD样行为有关。临床证据表明，免疫损伤会加重人类的ASD症状。
本研究旨在探讨脂多糖（LPS）在VPA诱导的自闭症雄性模型中诱导神经炎症的可能性。
在妊娠第12.5天，给怀孕的Sprague Dawley大鼠注射500mg/kg的VPA，以在其后代中建立ASD大鼠模型。VPA注射组的雄性后代在出生后第20天接受10mg/kg的LPS。采用免疫组织化学、蛋白质印迹和免疫荧光法评估前额叶皮质和海马中NF-κB信号通路相关蛋白和小胶质细胞的表达。进行基因本体论和通路富集分析以预测关键突触蛋白的功能，并通过实时聚合酶链反应分析进一步验证。
结果表明，VPA暴露导致雄性大鼠的运动活动增加、社交障碍和重复行为。VPA诱导组中NF-κB信号通路相关蛋白上调，小胶质细胞数量增加。此外，在暴露于VPA的后代大脑中观察到突触功能障碍。重要的是，LPS给药通过促进NF-κB信号通路激活、增加小胶质细胞数量和下调关键突触蛋白，加剧了VPA暴露雄性大鼠的自闭症相关行为。
本研究不仅有助于理解NF-κB信号通路、小胶质细胞和突触蛋白在ASD进展中的重要性，还确定了LPS在丙戊酸诱导的自闭症雄性模型中诱导神经炎症。
