Platelet Serotonin Transporter Function Predicts Default-Mode Network Activity

Background: 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. Methods: 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. Results: 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 SLC6A4. Furthermore, functional connectivity analyses indicate that platelet V-max is related to global DMN activation and not intrinsic DMN connectivity. Conclusion: 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.