State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Department of Neurology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210032, China.
Department of Anesthesiology and Perioperative Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Mol Psychiatry. 2022 Oct;27(10):4092-4102. doi: 10.1038/s41380-022-01659-8. Epub 2022 Jun 13.
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.
人类的不当攻击行为会伤害社会、家庭和个人。然而，攻击行为的遗传基础在很大程度上仍然难以捉摸。在这项研究中，我们从表现出以攻击爆发为特征的综合征的男性患者中鉴定出 X 连锁 GRIA3 中的两个罕见错义变体。AMPA 受体 GluA3 中的 G630R 和 E787G 突变完全丧失了其离子通道功能。此外，位于人类 GRIA3 基因第一内含子中的鸟嘌呤重复单核苷酸多态性（SNP，rs3216834）被发现可通过更长的鸟嘌呤重复（rs3216834-10G/-11G）来调节 GluA3 的表达，与较短的重复（-7G/-8G/-9G）相比，其转录受到抑制。重要的是，rs3216834-10G/-11G 的分布在来自中国汉族的男性暴力罪犯样本中升高。使用 GluA3 敲除小鼠，我们表明内侧前额叶皮质（mPFC）中的兴奋性神经传递和神经元活动受损。将 GluA3 重新表达到 mPFC 中减轻了 GluA3 敲除小鼠的攻击行为，这表明 mPFC 中的缺陷至少部分解释了攻击行为的神经机制。因此，我们的研究提供了令人信服的证据，表明 AMPA 受体 GluA3 的功能障碍会促进攻击行为。
