Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b

Zhihao Sheng, Qidong Liu, Chun Cheng, Mengzhu Li, Jed Barash, W. Andrew Kofke, Yuan Shen, Zhongcong Xie

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Environmental factors contribute to autism spectrum disorder. Fentanyl, one of the most widely used opioid analgesics in anaesthesia, can induce neurotoxicity, but its role in autism remains unknown. We determined whether fentanyl induced autism-like behaviours in young mice and the underlying mechanisms. Methods: Young male and female mice received fentanyl at postnatal days 6, 8, and 10, and performed behavioural tests, including three-chamber social preference, elevated plus maze, grooming behaviour, and open-field test, from postnatal days 30–32. Expression of Grin2b, the gene encoding the GluN2B subunit of the N-methyl-D-aspartate receptor, was assessed in the anterior cingulate cortex of male mice using fluorescence in situ hybridisation histochemistry. We used bisulfite target sequencing to determine Grin2b hypermethylation sites after fentanyl treatment. In the specific activation and rescue experiments, we injected the mu opioid receptor agonist [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (DAMGO) or Grin2b overexpression lentivirus into the anterior cingulate cortex of male mice. Results: Fentanyl induced autism-like behaviours in both young male and female mice, and downregulated Grin2b expression (0.49-fold [0.08] vs 1.00-fold [0.09]; P<0.01) and GluN2B protein amounts (0.38-fold [0.07] vs 1.00-fold [0.12]; P<0.01) in the anterior cingulate cortex through hypermethylation of Grin2b. The mu-opioid receptor antagonist naloxone and overexpression of Grin2b in anterior cingulate cortex attenuated the fentanyl-induced effects, whereas DAMGO injection into the anterior cingulate cortex induced autism-like behaviours. Conclusions: These data suggest that fentanyl induces autism-like behaviours in young mice via an epigenetic mechanism. Further research is required to determine possible clinical relevance to autism risk.

Original languageEnglish (US)
Pages (from-to)544-554
Number of pages11
JournalBritish Journal of Anaesthesia
Volume129
Issue number4
DOIs
StatePublished - Oct 2022

All Science Journal Classification (ASJC) codes

  • Anesthesiology and Pain Medicine

Fingerprint

Dive into the research topics of 'Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b'. Together they form a unique fingerprint.

Cite this