| First Author | Peng SX | Year | 2021 |
| Journal | Sci Rep | Volume | 11 |
| Issue | 1 | Pages | 11997 |
| PubMed ID | 34099816 | Mgi Jnum | J:322011 |
| Mgi Id | MGI:6720108 | Doi | 10.1038/s41598-021-91415-9 |
| Citation | Peng SX, et al. (2021) SNP rs10420324 in the AMPA receptor auxiliary subunit TARP gamma-8 regulates the susceptibility to antisocial personality disorder. Sci Rep 11(1):11997 |
| abstractText | 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 gamma-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 gamma-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 gamma-8 knockout and heterozygous mice and found that consistent with ASPD patients who often exhibit impulsivity, aggression, risk taking, irresponsibility and callousness, a decreased gamma-8 expression in mice displayed similar behaviors. Furthermore, we found that a decrease in TARP gamma-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 gamma-8 expression level is associated with ASPD, and that the TARP gamma-8 knockout mouse is a valuable animal model for studying this psychiatric disease. |
