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SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder
- Source :
- Scientific Reports, Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
- Publication Year :
- 2021
-
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.
- Subjects :
- Science
Hippocampus
AMPA receptor
Biology
Neurotransmission
Synaptic Transmission
Ion channels in the nervous system
Article
Human behaviour
medicine
Animals
Humans
Clustered Regularly Interspaced Short Palindromic Repeats
Receptors, AMPA
Prefrontal cortex
Cerebral Cortex
Mice, Knockout
Multidisciplinary
Behavior, Animal
Pyramidal Cells
Human brain
Antisocial Personality Disorder
DNA
Animal behaviour
Cortex (botany)
medicine.anatomical_structure
HEK293 Cells
Receptors, Glutamate
Social behaviour
Knockout mouse
Excitatory postsynaptic potential
Medicine
Calcium Channels
Gene expression
Neuroscience
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific reports
- Accession number :
- edsair.doi.dedup.....0691329670ae8181b5291b50f3801baa