Insula serotonin 2A receptor binding and gene expression contribute to serotonin transporter polymorphism anxious phenotype in primates.
Santangelo, Andrea Mariana
Riss, Patrick J
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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Santangelo, A. M., Sawiak, S., Fryer, T., Hong, Y., Shiba, Y., Clarke, H., Riss, P. J., et al. (2019). Insula serotonin 2A receptor binding and gene expression contribute to serotonin transporter polymorphism anxious phenotype in primates.. Proceedings of the National Academy of Sciences of the United States of America, 116 (29), 14761-14768. https://doi.org/10.1073/pnas.1902087116
Genetic variation in the serotonin transporter gene (SLC6A4) is associated with vulnerability to affective disorders and alterations in the efficacy of pharmacological treatment. We recently identified sequence polymorphisms in the common marmoset SLC6A4 repeat region (AC/C/G and CT/T/C) associated with individual differences in trait anxiety, gene expression and response to antidepressants. The mechanisms underlying the effects of these polymorphisms are unknown, but a key mediator of serotonin action is the serotonin 2A receptor (5HT2A). Thus, we correlated 5HT2A binding potential (BP) and post mortem RNA gene expression in 16 SLC6A4 genotyped marmosets with responsivity to 5HT2A antagonism during the human intruder test of anxiety. Voxel-based analysis and RNA measurements showed a reduction in 5HT2A BP and gene expression specifically in the right posterior insula of individuals homozygous for the anxiety-related variant AC/C/G. These same marmosets displayed an enhanced anxiety-related, dose-dependent response to the human intruder after 5HT2A pharmacological antagonism, whilst CT/T/C individuals showed no effect. A voxel-based correlation analysis, independent of SLC6A4 genotype, revealed that 5HT2A BP in the adjacent right anterior insula and insula proisocortex was negatively correlated with trait anxiety scores. Moreover, 5HT2A BP in both regions were good predictors of the size and direction of the acute emotional response to the human intruder threat after 5HT2A antagonism. Our findings suggest that genetic variation in the SLC6A4 repeat region may contribute to the trait anxious phenotype via neurochemical changes in brain areas implicated in interoceptive and emotional processing, with a critical role for the right insula 5HT2A in the regulation of affective responses to threat.
Cerebral Cortex, Animals, Callithrix, Humans, Fluorobenzenes, Piperidines, Receptor, Serotonin, 5-HT2A, RNA, Injections, Intramuscular, Models, Animal, Behavior, Animal, Stress, Psychological, Anxiety, Genotype, Polymorphism, Genetic, Female, Male, Serotonin Plasma Membrane Transport Proteins, Promoter Regions, Genetic, Serotonin 5-HT2 Receptor Antagonists
WELLCOME TRUST (108089/Z/15/Z)
Medical Research Council (MR/M023990/1)
External DOI: https://doi.org/10.1073/pnas.1902087116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293812
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