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.
Highlights
Human emotion arises from interactions between brain regions within the limbic system, including the amygdala, hippocampus, insula, and cingulate c ortex[1,2,3]
It was reported that a two-SNP haplotype in the intronic region of CACNG8 was associated with schizophrenia[29]
We aim to understand the role of the AMPA receptor regulatory protein transmembrane AMPA-type glutamate receptors (AMPARs) regulatory proteins (TARPs) γ-8 in emotional disorders
Summary
Human emotion arises from interactions between brain regions within the limbic system, including the amygdala, hippocampus, insula, and cingulate c ortex[1,2,3]. Dysregulation of AMPAR trafficking results in impaired synaptic plasticity, abnormal neuronal networks, altered emotions or behaviors, and neuronal d iseases[8,9,10,11]. Six TARPs have been classified as type 1 (γ-2, γ-3, γ-4, and γ-8) or type 2 (γ-5 and γ-7) based on their sequence similarities and functional properties[17] In the brain, these six proteins have different expression p atterns[19]. High TARP γ-8 expression was detected in the cortex, hippocampus and subcortical regions[19], brain areas that are critical for emotion generation. This expression pattern suggests that TARP γ-8 may affect emotion-related behaviors. The exact role and the molecular mechanisms of TARP γ-8 in emotion remain elusive
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