Association of Protein Distribution and Gene Expression Revealed by PET and Post-Mortem Quantification in the Serotonergic System of the Human Brain

Abstract

Regional differences in posttranscriptional mechanisms may influence in vivo protein densities. The association of positron emission tomography (PET) imaging data from 112 healthy controls and gene expression values from the Allen Human Brain Atlas, based on post-mortem brains, was investigated for key serotonergic proteins. PET binding values and gene expression intensities were correlated for the main inhibitory (5-HT1A) and excitatory (5-HT2A) serotonin receptor, the serotonin transporter (SERT) as well as monoamine oxidase-A (MAO-A), using Spearman's correlation coefficients (rs) in a voxel-wise and region-wise analysis. Correlations indicated a strong linear relationship between gene and protein expression for both the 5-HT1A (voxel-wise rs = 0.71; region-wise rs = 0.93) and the 5-HT2A receptor (rs = 0.66; 0.75), but only a weak association for MAO-A (rs = 0.26; 0.66) and no clear correlation for SERT (rs = 0.17; 0.29). Additionally, region-wise correlations were performed using mRNA expression from the HBT, yielding comparable results (5-HT1Ars = 0.82; 5-HT2Ars = 0.88; MAO-A rs = 0.50; SERT rs = -0.01). The SERT and MAO-A appear to be regulated in a region-specific manner across the whole brain. In contrast, the serotonin-1A and -2A receptors are presumably targeted by common posttranscriptional processes similar in all brain areas suggesting the applicability of mRNA expression as surrogate parameter for density of these proteins.

Keywords: 5-HT1A; 5-HT2A; MAO-A; SERT; mRNA.

Figure 1.

Brain topology of mRNA samples in the MNI stereotactic space. Coordinates from the AHBA are visualized by (A) yellow dots (8 mm³) on the MR-based brain rendering. The size of each dot exceeds the size of histological samples (0.9 mm³) for a better visualization. (B) White dots within color-coded AAL regions on the triplanar MNI brain template (x = 90, y = 126, z = 72).

Figure 2.

Region-wise correlations between mRNA expression (log₂) and binding potential (BP) or distribution volume (V_T), indices for protein concentration quantified by PET. Each dot represents averaged mRNA from the AHBA and PET values within one anatomical region. Post-mortem mRNA samples and in vivo imaging values were combined into a single brain template, for the (A) 5-HT_1A receptor (radioligand: [carbonyl-¹¹C]WAY-100635), (B) 5-HT_2A receptor ([¹⁸F]altanserin), (C) serotonin transporter (SERT, [¹¹C]DASB), and (D) monoamine oxidase-A (MAO-A, [¹¹C]harmine).

Figure 3.

Voxel-wise correlation between mRNA expression (log₂) and binding potential (BP_ND) for the 5-HT_1A receptor (radioligand: [carbonyl-¹¹C]WAY-100635). Each dot represents mRNA from the AHBA and PET values in target coordinates. Post-mortem samples of 6 donors and cooresponding PET binding values were combined into a single brain template.

Figure 4.

Region-wise correlation between cortical (blue) and subcortical (red) mRNA expression (log₂) and binding potential (BP) for the 5-HT_1A receptor. Each dot represents averaged mRNA from the AHBA and PET values within cortical and subcortical regions. Post-mortem samples of 6 donors and corresponding PET binding values were combined into a single brain template.

Figure 5.

Topological distribution of serotonergic key proteins across 46 anatomical regions of interest in the human brain showed in a polar graph. The radial axis indicates PET binding (solid line) and mRNA expression derived from the AHBA (dashed line). All values were averaged for the left and right hemisphere. Absolute values of protein binding were normalized into relative values ranging from 0 to 1 for both modalities to visualize regional differences of protein distribution for the (A) 5-HT_1A (yellow) and (B) 5-HT_2A (blue) receptor, (C) the SERT (green) as well as (D) MAO-A (red).

Figure 5.

Topological distribution of serotonergic key proteins across 46 anatomical regions of interest in the human brain showed in a polar graph. The radial axis indicates PET binding (solid line) and mRNA expression derived from the AHBA (dashed line). All values were averaged for the left and right hemisphere. Absolute values of protein binding were normalized into relative values ranging from 0 to 1 for both modalities to visualize regional differences of protein distribution for the (A) 5-HT_1A (yellow) and (B) 5-HT_2A (blue) receptor, (C) the SERT (green) as well as (D) MAO-A (red).

Figure 6.

Topological distribution of the 5-HT_1A (yellow), 5-HT_2A (blue) receptor, the SERT (green) as well as MAO-A (red) across 46 anatomical regions of interest in the human brain. All values were averaged for the left and right hemisphere. Absolute values of PET binding were normalized for each radiotracer to visualize regional differences of protein distribution. For gene expression, data were normalized between proteins to visualize relative differences of mRNA expression. The radial axis indicates (A) mRNA expression derived from the AHBA (dashed lines) and (B) PET binding (solid lines).