Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human
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Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human. / Peng, Shi Xiao; Pei, Jingwen; Rinaldi, Berardo; Chen, Jiang; Ge, Yu Han; Jia, Min; Wang, Jun; Delahaye-Duriez, Andrée; Sun, Jia Hui; Zang, Yan Yu; Shi, Yong Yun; Zhang, Ning; Gao, Xiang; Milani, Donatella; Xu, Xijia; Sheng, Nengyin; Gerard, Benedicte; Zhang, Chen; Bayat, Allan; Liu, Na; Yang, Jian Jun; Shi, Yun Stone.
In: Molecular Psychiatry, Vol. 27, No. 10, 10.2022, p. 4092-4102.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human
AU - Peng, Shi Xiao
AU - Pei, Jingwen
AU - Rinaldi, Berardo
AU - Chen, Jiang
AU - Ge, Yu Han
AU - Jia, Min
AU - Wang, Jun
AU - Delahaye-Duriez, Andrée
AU - Sun, Jia Hui
AU - Zang, Yan Yu
AU - Shi, Yong Yun
AU - Zhang, Ning
AU - Gao, Xiang
AU - Milani, Donatella
AU - Xu, Xijia
AU - Sheng, Nengyin
AU - Gerard, Benedicte
AU - Zhang, Chen
AU - Bayat, Allan
AU - Liu, Na
AU - Yang, Jian Jun
AU - Shi, Yun Stone
N1 - Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
U2 - 10.1038/s41380-022-01659-8
DO - 10.1038/s41380-022-01659-8
M3 - Journal article
C2 - 35697757
AN - SCOPUS:85131876195
VL - 27
SP - 4092
EP - 4102
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 10
ER -
ID: 389675852