SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder

Abstract 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...

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Autores principales:	Shi-Xiao Peng, Yue-Ying Wang, Min Zhang, Yan-Yu Zang, Dan Wu, Jingwen Pei, Yansong Li, Jiapei Dai, Xiaoyun Guo, Xingguang Luo, Ning Zhang, Jian-Jun Yang, Chen Zhang, Xiang Gao, Na Liu, Yun Stone Shi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7a275b7227e84e479d654815aa540827
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spelling	oai:doaj.org-article:7a275b7227e84e479d654815aa5408272021-12-02T17:47:03ZSNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder10.1038/s41598-021-91415-92045-2322https://doaj.org/article/7a275b7227e84e479d654815aa5408272021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91415-9https://doaj.org/toc/2045-2322Abstract 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.Shi-Xiao PengYue-Ying WangMin ZhangYan-Yu ZangDan WuJingwen PeiYansong LiJiapei DaiXiaoyun GuoXingguang LuoNing ZhangJian-Jun YangChen ZhangXiang GaoNa LiuYun Stone ShiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shi-Xiao Peng Yue-Ying Wang Min Zhang Yan-Yu Zang Dan Wu Jingwen Pei Yansong Li Jiapei Dai Xiaoyun Guo Xingguang Luo Ning Zhang Jian-Jun Yang Chen Zhang Xiang Gao Na Liu Yun Stone Shi SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder
description	Abstract 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.
format	article
author	Shi-Xiao Peng Yue-Ying Wang Min Zhang Yan-Yu Zang Dan Wu Jingwen Pei Yansong Li Jiapei Dai Xiaoyun Guo Xingguang Luo Ning Zhang Jian-Jun Yang Chen Zhang Xiang Gao Na Liu Yun Stone Shi
author_facet	Shi-Xiao Peng Yue-Ying Wang Min Zhang Yan-Yu Zang Dan Wu Jingwen Pei Yansong Li Jiapei Dai Xiaoyun Guo Xingguang Luo Ning Zhang Jian-Jun Yang Chen Zhang Xiang Gao Na Liu Yun Stone Shi
author_sort	Shi-Xiao Peng
title	SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder
title_short	SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder
title_full	SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder
title_fullStr	SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder
title_full_unstemmed	SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder
title_sort	snp rs10420324 in the ampa receptor auxiliary subunit tarp γ-8 regulates the susceptibility to antisocial personality disorder
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7a275b7227e84e479d654815aa540827
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SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder

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