SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder.
SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder.
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AMPA 受体辅助亚基 TARP gamma-8 中的 SNP rs10420324 调节反社会人格障碍的易感性
DOI：
10.1038/s41598-021-91415-9
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发表时间：
2021-06-07
影响因子：
4.6
通讯作者：
Shi YS
中科院分区：
文献类型：
--
作者：
Peng SX;Wang YY;Zhang M;Zang YY;Wu D;Pei J;Li Y;Dai J;Guo X;Luo X;Zhang N;Yang JJ;Zhang C;Gao X;Liu N;Shi YS
在大脑中，AMPA受体介导快速兴奋性神经传递，其功能障碍导致神经精神障碍。AMPA受体的突触功能由称为跨膜AMPAR调节蛋白（TARP）的蛋白质组严格控制。TARP γ-8（也称为CACNG 8）优先在海马、皮质和皮质下区域表达，这些区域对情绪产生至关重要，表明其与精神疾病相关。在这里，我们确定了rs 10420324（T/G），一个位于人CACNG 8基因的SNP，在体外调节报告基因表达和TARP γ-8在人脑中的表达。该位点的鸟嘌呤（rs 10420324 G）可能通过调节局部G-四链体DNA结构来抑制转录。与这些观察结果一致，rs 10420324 G在反社会人格障碍（ASPD）患者中的频率高于对照组，表明CACNG中的rs 10420324 G对ASPD更具自愿性。然后，我们对TARP γ-8基因敲除小鼠和杂合小鼠的行为进行了表征，发现与经常表现出冲动、攻击性、冒险、不负责任和冷酷无情的ASPD患者一致，小鼠中γ-8表达下降也表现出类似的行为。此外，我们发现TARP γ-8表达的减少损害了前额叶皮层的第2-3层锥体神经元中的突触AMPAR功能，前额叶皮层是一个抑制导致攻击的大脑区域，因此至少部分地解释了行为异常的神经元基础。综上所述，我们的研究表明TARP γ-8表达水平与ASPD相关，TARP γ-8基因敲除小鼠是研究ASPD的一种有价值的动物模型。
In the brain, AMPA receptors mediate fast excitatory neurotransmission, the dysfunction of which leads to neuropsychiatric disorders. Synaptic function of AMPA receptors is tightly controlled by a protein group called transmembrane AMPAR regulatory proteins (TARPs). TARP γ-8 (also known as CACNG8) preferentially expresses in the hippocampus, cortex and subcortical regions that are critical for emotion generation indicating its association with psychiatric disorders. Here, we identified rs10420324 (T/G), a SNP located in the human CACNG8 gene, regulated reporter gene expression in vitro and TARP γ-8 expression in the human brain. A guanine at the locus (rs10420324G) suppressed transcription likely through modulation of a local G-quadruplex DNA structure. Consistent with these observations, the frequency of rs10420324G was higher in patients with anti-social personality disorder (ASPD) than in controls, indicating that rs10420324G in CACNG8 is more voluntary for ASPD. We then characterized the behavior of TARP γ-8 knockout and heterozygous mice and found that consistent with ASPD patients who often exhibit impulsivity, aggression, risk taking, irresponsibility and callousness, a decreased γ-8 expression in mice displayed similar behaviors. Furthermore, we found that a decrease in TARP γ-8 expression impaired synaptic AMPAR functions in layer 2–3 pyramidal neurons of the prefrontal cortex, a brain region that inhibition leads to aggression, thus explaining, at least partially, the neuronal basis for the behavioral abnormality. Taken together, our study indicates that TARP γ-8 expression level is associated with ASPD, and that the TARP γ-8 knockout mouse is a valuable animal model for studying this psychiatric disease.
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