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

Abstract

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.

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Fig. 1: Mutations in GluA3 serve as a marker for patients with aggressive outbursts.
Fig. 2: GluA3 variants disrupt ion channel function.
Fig. 3: The SNP rs3216834 regulates GRIA3 gene expression.
Fig. 4: The SNP rs3216834 is associated with individuals who committed violent crimes.
Fig. 5: Behavioral analysis of Gria3Y/− mice.
Fig. 6: The excitation of neurons in mPFC is decreased in Gria3Y/− mice.

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Acknowledgements

We thank Dr. Zhengping Jia in University of Toronto for the generous gift of GluA3 KO mice. Fundings: This work is supported by grants from the National Key R&D Program of China (2019YFA0801603 to Y.S.S. and 2017YFA0105201 to C.Z.), the National Natural Science Foundation of China (32170951 and 91849112 to Y.S.S., 81901161 to J.C., 82171189 and 81971020 to J.J.Y., 31871032 to N.S. and 81901390 to N.L.), the Natural Science Foundation of Jiangsu Province (BE2019707 to Y.S.S.), Special Fund for Science and Technology Innovation Strategy of Guangdong Province (2021B0909050004 to Y.S.S.), the Fundamental Research Funds for the Central Universities (0903-14380029 to Y.S.S.), Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB17 to NS), and Yunnan Applied Basic Research Projects (2019FA008 and 2019FJ003 to N.S.).

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SXP, MJ, and YYZ conducted animal behavioral and molecular experiments. JP, JW, NZ, XG, XX, and NL designed questionnaire and provided human samples. BR, ADD, AB, DM, and BG collected GRIA3 pathogenic variants in subjects referred for neurodevelopmental disorders. JC, SXP, YHG, and JHS conducted electrophysiological experiments. YYZ and YYS took care of the animals in the study. NS, CZ, and JJY provided critical reagents and supervised the study. YSS designed the study and wrote the paper.

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Correspondence to Na Liu, Jian-Jun Yang or Yun Stone Shi.

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Peng, SX., Pei, J., Rinaldi, B. et al. Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human. Mol Psychiatry 27, 4092–4102 (2022). https://doi.org/10.1038/s41380-022-01659-8

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