Phenotyping extracellular vesicles and their serotonin transporter cargo in major depressive disorder

Abstract With their ability to cross the blood-brain barrier, transport and regulate the release of various signaling molecules, extracellular vesicles (EVs) constitute a novel avenue to study intercellular communication in various pathologies, including psychiatric disorders. We studied 34 major depressive disorder (MDD) patients and 57 healthy controls and characterized EVs isolated from plasma using digital holographic tomography (DHT) and nanoparticle tracking analysis (NTA). EVs detected in DHT were markedly smaller and less variable in size in MDD patients. Furthermore, a lower variance of refractive indices related to the dry mass density of EVs was observed in patients. Meanwhile, NTA revealed a trend for elevated concentration of EVs in MDD. In DHT, EV dimensions correlated with plasma mRNA expression of exosomal markers CD63 and CD9 , with corresponding alterations in MDD. Levels of EV concentration and CD9 were both negatively correlated with antidepressant treatment response. Utilizing electron microscopy and immunoblots we confirmed the presence of serotonin transporters (SERT) as EV cargo. SERT levels in EVs correlated with cerebral SERT binding potential in the amygdala measured using positron emission tomography. Next to the implication of altered EV communication in mood disorders, the pronounced differences in plasma EV characteristics and exosomal markers in MDD might inform the development of assays with diagnostic or prognostic value for clinical practice.