Autistic-like behaviors and impaired chronic inflammatory pain in primary nociceptive neuron-specific deletion of Mecp2 or Fmr1 knockout male mice.

AIMS

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.