Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human

Shi Xiao Peng, Jingwen Pei, Berardo Rinaldi, Jiang Chen, Yu Han Ge, Min Jia, Jun Wang, Andrée Delahaye-Duriez, Jia Hui Sun, Yan Yu Zang, Yong Yun Shi, Ning Zhang, Xiang Gao, Donatella Milani, Xijia Xu, Nengyin Sheng, Benedicte Gerard, Chen Zhang, Allan Bayat, Na LiuJian Jun Yang, Yun Stone Shi*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


Inappropriate aggression in humans hurts the society, families and individuals. The genetic basis for aggressive behavior, however, remains largely elusive. In this study, we identified two rare missense variants in X-linked GRIA3 from male patients who showed syndromes featuring aggressive outbursts. Both G630R and E787G mutations in AMPA receptor GluA3 completely lost their ion channel functions. Furthermore, a guanine-repeat single nucleotide polymorphism (SNP, rs3216834) located in the first intron of human GRIA3 gene was found to regulate GluA3 expression with longer guanine repeats (rs3216834-10G/-11G) suppressing transcription compared to the shorter ones (-7G/-8G/-9G). Importantly, the distribution of rs3216834-10G/-11G was elevated in a male violent criminal sample from Chinese Han population. Using GluA3 knockout mice, we showed that the excitatory neurotransmission and neuronal activity in the medial prefrontal cortex (mPFC) was impaired. Expressing GluA3 back into the mPFC alleviated the aggressive behavior of GluA3 knockout mice, suggesting that the defects in mPFC explained, at least partially, the neural mechanisms underlying the aggressive behavior. Therefore, our study provides compelling evidence that dysfunction of AMPA receptor GluA3 promotes aggressive behavior.

Original languageEnglish
JournalMolecular Psychiatry
Pages (from-to)4092–4102
Publication statusPublished - 13. Jun 2022

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© 2022, The Author(s), under exclusive licence to Springer Nature Limited.


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