Scientific Reports (Jun 2021)

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

  • 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

DOI
https://doi.org/10.1038/s41598-021-91415-9
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 15

Abstract

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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.