A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala

Converging evidence in neurophysiological and neuroimaging studies has suggested that the limbic and prefrontal systems play important roles in emotion and cognition. These structures are activated when we see a human face, assuming that we automatically evaluate the biological significance of the stimuli. The serotonin (5-HT) system within the brain has been tied to various behaviors such as mood and anxiety and to the biology of neuropsychiatric disorders. To investigate the link between the 5-HT system and limbic/prefrontal activity, normal subjects (n = 26) who underwent functional magnetic resonance imaging and faced recognition tasks were genotyped for the single nucleotide polymorphism C178T in the regulatory region of the serotonin receptor type 3 gene (HTR3A). We found that the subjects with C/C alleles had greater activity in the amygdala and dorsal and medial prefrontal cortices than those with C/T alleles. The C/C group also showed a faster reaction time during the task than the C/T group. The temperamental predisposition of the subjects had a significant correlation with brain activity in the C/C group. The genotype effect in the right amygdala and prefrontal cortex was largest during the first run of the experiment. These results indicate that the C178T variation in the HTR3A has a critical influence on the amygdaloid activity and on human face processing, probably through regulation of the receptor expression. The present study may contribute to elucidating a possible link among genes, the brain, and behavior in normal populations and may help reveal the biological basis of neuropsychiatric disorders.