Jing Peng-Bo, Zhou Yin-Wei, Zhang Feng-Ming, Ge Jia-Yi, Wu Jia-Ni, Xu Jia-Huan, Cao Xiao-Hua, Chang Na, Zhou Xiang, Luo Lin, Liu Xing-Jun
School of Pharmacy, Nantong University, Nantong, Jiangsu 226019, China.
School of Pharmacy, Nantong University, Nantong, Jiangsu 226019, China.
Behav Brain Res. 2025 May 28;486:115570. doi: 10.1016/j.bbr.2025.115570. Epub 2025 Mar 31.
Recent studies have identified the roles of autism risk genes in primary sensory neurons and their connection to autism spectrum disorder (ASD) etiology. However, further research is needed to determine the specific impact of different sensory neuron populations. The aim of this study was to investigate the actions of Mecp2 or Fmr1 expression in primary nociceptive neurons on ASD and pain perception.
Conditional knockout mice lacking Mecp2 or Fmr1, both known to be associated with ASD, were generated specifically in nociceptive neurons of dorsal root ganglion (DRG) and trigeminal ganglion. A series of behavioral tests were used to assess ASD-relevant and pain-related behaviors in normal and inflammatory pain states. Formalin and complete Freund's adjuvant (CFA) injection were used to evoke acute and chronic inflammatory pain. Immunofluorescent approach was employed to study neuroinflammation and calcitonin gene-related peptide (CGRP) expression.
Both lines exhibited autistic-like behaviors, with reduced social interactions in SNS/Mecp2 mice and increased repetitive behaviors in SNS/Fmr1 mice. Although SNS/Mecp2 and SNS/Fmr1 mice displayed normal baseline pain, formalin-evoked acute and subacute pain sensation, CFA-evoked persistent inflammatory pain was impaired, especially less thermal hyperalgesia. Consistently, neuroinflammation and neural CGRP expression in SNS/Mecp2 and SNS/Fmr1 mice was reduced in response to CFA-injection.
Absent Mecp2 or Fmr1 in primary nociceptive neurons plays role in the pathogenesis of ASD and that their expression in primary nociceptors is crucial for the maintenance of chronic inflammatory pain by reducing neuroinflammation and CGRP expression in the peripheral and central nervous systems.
近期研究已确定自闭症风险基因在初级感觉神经元中的作用及其与自闭症谱系障碍（ASD）病因的关联。然而，需要进一步研究以确定不同感觉神经元群体的具体影响。本研究的目的是探究初级伤害性神经元中Mecp2或Fmr1表达对ASD和痛觉的作用。
分别在背根神经节（DRG）和三叉神经节的伤害性神经元中特异性敲除已知与ASD相关的Mecp2或Fmr1，构建条件性敲除小鼠。采用一系列行为测试评估正常和炎性疼痛状态下与ASD相关及与疼痛相关的行为。通过注射福尔马林和完全弗氏佐剂（CFA）诱发急性和慢性炎性疼痛。采用免疫荧光法研究神经炎症和降钙素基因相关肽（CGRP）表达。
两种品系的小鼠均表现出自闭症样行为，SNS/Mecp2小鼠的社交互动减少，SNS/Fmr1小鼠的重复行为增加。尽管SNS/Mecp2和SNS/Fmr1小鼠的基线疼痛正常，福尔马林诱发的急性和亚急性痛觉正常，但CFA诱发的持续性炎性疼痛受损，尤其是热痛觉过敏较轻。同样，注射CFA后，SNS/Mecp2和SNS/Fmr1小鼠的神经炎症和神经CGRP表达降低。
初级伤害性神经元中Mecp2或Fmr1缺失在ASD发病机制中起作用，且它们在初级伤害感受器中的表达对于通过减少外周和中枢神经系统的神经炎症和CGRP表达来维持慢性炎性疼痛至关重要。
