In this study, we examined the association between in-vivo protein expression of DAT from PET, and DAT mRNA expression from Allen Human Brain Atlas. Among 6 probes for DAT mRNA from Allen Human Brain Atlas database, 5 probes showed much lower expression levels of DAT mRNA than probe 6, probably due to a lack of sensitivity. Although mRNA expression of probe 6 showed the highest expression levels in each VOI, the auto-correlation between subjects (inter-subject correlation) was weak with mean 𝛒2 of 0.2263, and cross-correlation with PET-derived BPNDs was also weak with mean 𝛒2 of 0.2220. However, mean mRNA expression of probe 6 showed the significant correlation with mean PET-derived BPND.
Previously, the predictive power of brain mRNA mappings of Allen Human Brain Atlas was investigated after comparison with PET-derived protein expressions including serotonin receptor (7–9), serotonin transporter (8, 9), opioid receptor (7), monoamine oxidase A (MAO-A) (9, 10). The association between mRNA expressions, and PET-derived protein expression were strong in serotonin receptors (7–9), or weak in opioid receptor (7). However, in studies of MAO-A mRNA expressions, inconsistent results were reported as weak correlation with 11C-Harmine (9), and strong correlation with 11C-Befloxatone (10).
Dopamine is a neurotransmitter that involves in reward-motivated behavior, and motor control (1). Brain dopamine neurotransmission is regulated by DAT, which drives reuptake of extracellular dopamine into presynaptic neurons (2). Dysfunction of DAT has been known to be linked to neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder (3), biopolar disorder (4), and alcoholism (5). In addition, DAT is a major target for various pharmacologically active drugs (2). From genomic maps such as Allen Human Brain Atlas, gene expression can be visualized across whole brain regions yielding insights into the relationship between structure and function of human brain (15), leading to help brain investigation, and drug development (7). Therefore, we investigated the association of DAT between protein expression measured by PET, and mRNA expression from Allen Human Brain Atlas. However, in this study, we observed relatively weak associations between DAT protein expressions, and DAT mRNA expressions regardless of probes. In addition, the correlation between mean PET-derived BPNDs, and mean DAT mRNA expression levels were marginally significant in 1 of 6 probes. Therefore, maps of the human mRNA transcription architecture from DNA microarray analysis of DAT might have limited predictive value, after comparison with PET-derived protein expression in this study. Previously, Rizzo et al. explained the possible mechanisms of the limited predictive role of mRNA mapping for protein expression (7). First, posttranscriptional mechanisms of splicing, or translational modifications might influence protein expression for each cell type (7, 16). In addition, mRNA expression is analyzed in the cytoplasm, while DAT protein is predominantly expressed presynaptically (9), which might affect the limited role of mRNA mapping for DAT.
There are several limitations in this study. First, the sample size of Allen Human Brain Atlas database is small with 6 donors. Second, although mRNA data of 6 probes were included across the regions, mRNA expression from 5 probes were systemically low, probably due to a lack of sensitivity of probes. In addition, the auto-correlation of mRNA expression between individuals was weak, probably due to interindividual variations. Also, DAT of both mRNA expressions, and PET-derived BPNDs might be affected by the functional status of dopaminergic system, dopamine levels in the brain. Lastly, substantia nigra and ventral tegmental area might have a relevant role in the description of mRNA for DAT protein expression.