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

• Published in: Scientific reports Vol. 11; no. 1; p. 11997
• Main Authors: Peng, Shi-Xiao, Wang, Yue-Ying, Zhang, Min, Zang, Yan-Yu, Wu, Dan, Pei, Jingwen, Li, Yansong, Dai, Jiapei, Guo, Xiaoyun, Luo, Xingguang, Zhang, Ning, Yang, Jian-Jun, Zhang, Chen, Gao, Xiang, Liu, Na, Shi, Yun Stone
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 07.06.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Aggression; Animal models; Animals; Antisocial personality disorder; Antisocial Personality Disorder - metabolism; Behavior, Animal; CACNG8 gene; Calcium Channels - metabolism; Cerebral Cortex - metabolism; Clustered Regularly Interspaced Short Palindromic Repeats; DNA structure; Gene expression; Guanine; HEK293 Cells; Hippocampus - metabolism; Humans; Impulsive behavior; Mental disorders; Mice; Mice, Knockout; Neurotransmission; Personality; Prefrontal cortex; Pyramidal cells; Pyramidal Cells - metabolism; Receptor mechanisms; Receptors, AMPA - metabolism; Receptors, Glutamate - metabolism; Regulatory proteins; Reporter gene; Risk taking; Single-nucleotide polymorphism; Social behavior; Synaptic Transmission; Transcription; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-91415-9

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.