Platelet Serotonin Transporter Function Predicts Default-Mode Network Activity

<div><p>Background</p><p>The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene <i>SLC6A4</i> and removes serotonin (5-HT) from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence.</p><p>Methods</p><p>A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (V_max) was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA) to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD) activity and platelet V_max.</p><p>Results</p><p>The present study demonstrates that increases in platelet V_max significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within <i>SLC6A4</i>. Furthermore, functional connectivity analyses indicate that platelet V_max is related to global DMN activation and not intrinsic DMN connectivity.</p><p>Conclusion</p><p>This study provides evidence that platelet V_max predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal V_max coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.</p></div

Functional brain correlates of platelet 5-HT uptake velocity.

<p>(<b>A–B</b>) Figures display right-hemispheric surface mappings of a whole-brain correlation analysis between platelet V_max and BOLD activity (n = 48). Significant brain areas showed positive and negative correlations. Negatively correlated clusters comprised areas of the DMN such as regions within the mPFC/ACC as well as the PCC, MTG, and ITG. Positive correlations were found in the fronto-parietal control system encompassing the CEN and SN with a significant cluster located in the right MOC and PMC. The corresponding left-hemispheric mapping is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092543#pone.0092543.s002" target="_blank">Figure S2</a>. Colorbar represents t-values. (<b>C</b>) Scatter plot shows the negative relationship between platelet V_max and BOLD activity averaged across the mPFC cluster (peak at [−7.7, 44.1, 27.5]). (<b>D</b>) Scatter plot shows the positive relationship between platelet V_max and BOLD activity averaged across the MOC cluster (peak at [20.8, −21.6, 69.1]). All analyses are controlled for age, gender and 5-HTTLPR. Serotonin, 5-HT; maximal 5-HT uptake velocity, V_max; default mode network, DMN; medial prefrontal cortex, mPFC; anterior cingulate cortex, ACC; posterior cingulate cortex, PCC; middle temporal gyrus, MTG; inferior temporal gyrus, ITG; central executive network, CEN; salience network, SN; motor cortex, MOC; premotor cortex, PMC; blood-oxygen-level dependent, BOLD; a.u., arbitrary units.</p

Correlation analysis between maximal platelet 5-HT uptake velocity (V_max) and neuronal activation (n = 48).

<p>Medial prefrontal cortex, mPFC; anterior cingulate cortex, ACC; motor cortex, MOC; premotor cortex, PMC; posterior cingulate cortex, PCC; precuneus, PRE; middle temporal gyrus, MTG; inferior temporal gyrus, ITG; p, uncorrected p value; significance level after correction for multiple comparisons based on recent recommendations <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092543#pone.0092543-Johnson1" target="_blank">[63]</a>: ***p<0.001; **p<0.005; *p<0.05; x, y, z are coordinates in Talairach space; L, left hemisphere; R, right hemisphere; cluster size expressed as number of voxels.</p