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

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.

Automated summary

TARP gamma-8 expression level is associated with antisocial personality disorder (ASPD), and rs10420324G in CACNG8 is more susceptible to ASPD. Decreased TARP gamma-8 expression in mice leads to behavioral abnormalities similar to ASPD patients, partially explaining the neuronal basis for ASPD.