Abstract
BackgroundThe serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene SLC6A4 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.MethodsA functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (Vmax) 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 Vmax.ResultsThe present study demonstrates that increases in platelet Vmax significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet Vmax is related to global DMN activation and not intrinsic DMN connectivity.ConclusionThis study provides evidence that platelet Vmax predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal Vmax coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.
Highlights
The serotonin transporter (5-HTT) is abundantly expressed throughout the human body by the 5-HTT gene (SLC6A4)
A comparison of platelet Vmax between low (S, LG) and high (LA) expressing variants based on the triallelic classification of 5-HTTLPR and rs25531 resulted in a borderline significant (t(15.29) = 1.8632, p = 0.0488, one-tailed) lower platelet Vmax in S and LG allele carriers compared to subjects with LA/LA genotype in line with previous results [41,42]
To investigate the potential predictive value of platelet Vmax with respect to task-related neural activation (Text S1 and Figure S1), a voxel-wise regression analysis between platelet Vmax and whole-brain blood-oxygen-level dependent (BOLD) signaling controlled for age, gender, and 5HTTLPR genotype was performed
Summary
The serotonin transporter (5-HTT) is abundantly expressed throughout the human body by the 5-HTT gene (SLC6A4). Highest amounts of 5-HTT protein can be found in the gastrointestinal tract, blood platelets, and serotonergic neurons in the brain [1]. Serotonin (5-HT) reuptake by transmembrane 5-HTTs represents the primary mechanism of 5HT clearance from blood plasma [1]. The 5-HTT protein is the central regulator of extracellular 5-HT levels in both platelets and serotonergic neurons [1,2]. 5-HTTs are involved in numerous physiologic brain functions including emotion processing [2], which is known to be altered in major depressive disorder (MDD) [3]. The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene SLC6A4 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
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