SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder.
Sci Rep
; 11(1): 11997, 2021 06 07.
Article
em En
| MEDLINE
| ID: mdl-34099816
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Canais de Cálcio
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Córtex Cerebral
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Receptores de AMPA
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Hipocampo
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Transtorno da Personalidade Antissocial
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article