The analysis of extracellular vesicles has been accelerated because of the technological advancements in omics methods in recent decades. Extracellular vesicles provide multifaceted information regarding the functional status of the cells. This information would be critical in case of central nervous system cells, which are confined in a relatively sealed biological compartment. This obstacle is more dramatic in psychiatric disorders since their diagnosis primarily depend on the symptoms and signs of the patients. In this paper, we reviewed this rapidly advancing field by discussing definition of extracellular vesicles, their biogenesis and potential use as clinical biomarkers. Then we focused on their potential use in psychiatric disorders in the context of diagnosis and treatment of these disorders. Finally, we tried to combine the RDoC (Research Domain Criteria) with the use of extracellular vesicles in psychiatry research and practice. This review may offer new insights in both basic and translational research focusing on psychiatric disorders.
The cells of multicellular organisms developed various ways of communication for maintaining homeostasis and response to their inner and outer environment [
The extracellular vesicles can be classified as exosomes, which has a diameter ranging from 30 nm to 100 nm; microvesicles with diameter between 100–1000 nm; apoptotic bodies, which are released from dying cells via apoptotic process, and has a diameter between 800–5000 nm, and large oncosomes, which are released from neoplastic cells and has a diameter larger than 1 μm and can be large as 10 μm [
The exosomes are generated via multivesicular bodies (MVB) which are derived from early endosomes. Early endosomes contain lipid rafts with specific proteins e.g. tetraspanins, adhesion, fusion, and receptor transport proteins. With the intraluminal vesicle (ILV) formation, these molecules are incorporated into the exosomal membrane [
Microvesicles are the generated through the budding of plasma membrane, which is regulated through translocation of phospholipids by floppase/flippase enzymes, organization of cytoskeleton under plasma membrane with ADP-ribosylation factor 6 (ARF6), Phospholipase D (PLD), Extracellularsignal regulated kinase (ERK) and Myosin light-chain kinase (MLCK) enzymes [
EVs can be isolated from serum, saliva, cerebrospinal fluid (CSF), urine, breast milk, synovial fluid, effusions, semen and cell cultures [
Since CNS is sealed by bones, connective tissues and bloodbrain barriers, also contains vital centers for cognition, sensory, motor and autonomic functions, the indications for taking direct biopsies for diagnostic purposes is limited only to some life threating conditions like infection/abscess or brain tumors [
An alternative and relatively noninvasive way to obtain information from CNS is to collect EVs which are shed from blood brain barrier [
The isolation and biochemical analysis of EVs in psychiatric disorders can offer wide diagnostic and therapeutic opportunities, in addition to provision of valuable information regarding pathophysiology of these diseases [
Nevertheless, the previous studies focusing on EVs in psychiatric disorders are predominantly executed in postmortem brain tissues of the patients [
In this part of the review, we will focus on some important psychiatric disorders, in which the use of EVs might be beneficial in terms of basic research, diagnosis (including secondary prevention of psychiatric disorders) and treatment. We decided to review EVs in depression, bipolar disorder, schizophrenia, and Alzheimer’s disease in the context of Research Domain Criteria (RDoC), since the constructs of these criteria attempt to reflect the etiology of psychiatric diseases in different dimension, extending from the molecules to the neural circuitries and anatomical structures [
Depression is a major public health problem linked with decreased functionality and may result in mortality [
According to an analysis using RDoC Negative Valence Systems matrix, depression is associated with disruptions in certain neural circuits, e.g. cortico-limbic circuitry, some key genes involved in neurotransmitter metabolism (MAOA, COMT, DATI, 5HTTR, 5HTRs), glucocorticoid receptor downregulation, CRH, sex steroid, oxytocin, vasopressin upregulation, dysregulations in autonomic nervous system, hypothalamic-pituitary-adrenal axis, neuro-inflammation and extended reactivity and behavioral changes (e.g. withdrawal, sadness) [
One of the components of Negative Valence Systems matrix, neuro-inflammation, occurs in depression patients within CNS and associated with the activation of microglial cells [
The bipolar disorders are characterized with mania or hypomania, which are accompanied with major depressive attacks. Bipolar disorder pathophysiology is explained though anatomical and functional changes in brain architecture (including altered connectivity in anterior cingulate cortex, prefrontal cortex and amygdala), and neuro-inflammation [
According to the RDoC positive valance system matrix, bipolar disorders are linked with abnormally elevated reward activation, and excess approach motivation, which leads to approach related hypomanic/manic symptoms [
The studies carried on EVs obtained from patients with bipolar disorder show concordance with RDoC matrices in terms of anatomical locations, where pathological processes take place. The brain specific miRNA-134 is responsible for the formation of dendritic spines and synapses and can be obtained via blood samples and used for monitoring and treatment of mania episodes in bipolar disorder [
Schizophrenia is characterized by reoccurring or chronic psychosis along with other positive and negative (involving mood and cognition deficits) symptoms [
According to the RDoC positive valance system matrix, schizophrenia is linked with altered reward valuation/prediction linked with prefrontal/striatal activation, reduced reward learning and action selection. The impairment in explicit positive reinforced learning can be explained with increased dopamine in basal ganglia and reduced dorsolateral prefrontal cortex activity, which also explains the impairment the action towards valuated outcomes [
The postmortem prefrontal cortex samples of schizophrenia patients have increased amounts of exosomal miR-497, when it’s compared to control patients [
Alzheimer’s disease (AD) is characterized with increasing decline of cognitive functions as a result of neural degeneration, especially in older individuals. The most noticeable feature of AD is the progressive memory loss but it’s commonly accompanied by other cognitive deficits e.g. behavioral, and psychological signs [
The pathophysiology of AD is characterized by accumulations of Tau and β-amyloid proteins in intra- and extracellular compartments, respectively [
The previous studies revealed that some fraction of β-amyloid protein secretion to extracellular compartment occurs through exosomes. Amyloid precursor protein (APP) is cleaved into β-amyloid proteins and fragments of β-carboxyl-terminal (CTFs) via secretase enzymes (β and γ, which are involved in AD pathogenesis) within exosomes. This cleavage process begins in endosomes and multivesicular bodies within the intracellular compartment, and continues in the exosomes in extracellular domain. The β and γ cleavage products of APP leads the formation of β-amyloid plaques in extracellular compartment of CNS [
Additionally, exosomes are also responsible for spreading of the hyper-phosphorylated Tau proteins in AD. Thus, these neurofibrillary tangles may contaminate the healthy neurons via EVs and interfere with the metabolism and intracellular neurotransmitter transport system of these cells [
Nevertheless, it is also demonstrated that the neural exosomes are responsible for clearance of β-amyloid plaques via microglia within CNS [
Along with the proteins, miRNAs are also released within exosomes and play significant roles in AD pathogenesis. The alterations in exosomal miRNA expressions in AD can be detected in CSF and/or peripheral blood samples. The role of miRNAs in neurodegeneration is multifaceted, while some miRNA molecules (like miRNA-219, miR-124a) favor myelination and signaling, others (like miR-193b, let-7) accelerate neural degeneration through increasing neuro-inflammation and amyloid plaque formation [
The RDoC constructs provide valuable information for choosing candidates for biomarker molecules for both diagnostic and therapeutic purposes in psychiatric disorders. By using methods of bioinformatics, these potential biomarkers can be extracted from RDoC domain matrices. Extracellular vesicles provide a chance for measuring different classes of biomarkers (e.g. miRNA, proteins and lipids) simultaneously, which might increase the predictive values of testing and help to overcome the difficulties of working with a diagnostic modality relying on a single class of molecule. Using multiple markers on extracellular vesicles carry a huge potential for improving of understanding and managing of psychiatric disorders.
Exosomes Biogenesis The biogenesis of exosomes occurs within the cells through a multistep process. In this figure, the exosome formation is simplified to emphasize the important steps in this cellular process. 1. The exosome formation starts with the inward budding of plasma membranes into the cytoplasm (endocytosis), which leads to the early endosome formation. 2. Early endosomes accumulate and fuse to form multivesicular bodies (MVB). 3. Nucleic acids (mRNA, miRNA, other RNA molecules and fragments of DNA) from the nucleus are transported into the MVB, and accumulate within this membrane bound structure. 4. Some mRNAs translated to protein structures through ribosomes and these proteins are transported into the MVB. 5. The outer membrane of MVB form another internal compartment by budding into this structure. This vesicle inside of MVB is called intraluminal vesicle (ILV). Proteins and nucleic acids are sorted into the ILVs through molecular sorting mechanisms composed of proteins like ESCRT (Endosomal sorting complexes required for transport), TSG 101 (Tumor susceptibility gene), and ALIX (ALG-2-interacting protein X). 6. Exosomes expelled from the cell via exocytosis, where MVB docks with plasma membrane via Rab proteins, and unloads its exosome cargo. The contents of exosomes are diverse, which are composed of various proteins and nucleic acids. 7. Exosomes are secreted to the extracellular compartment. These membrane bound structures can travel through blood and lymphatic vessels, cerebrospinal fluid (CSF), saliva and other secretions of the body. Exosomes possess adhesion and receptor proteins on their surfaces, which allows the exosomes to bind to their specific targets.
Microvesicle biogenesis The biogenesis of microvesicles occurs mainly on plasma membrane and adjacent cytoplasmic structures (including microfilaments and cytoplasm), through a multistep process. In this figure, the microvesicle formation is simplified to emphasize the important steps in this cellular process. 1. Nucleic acids from the nucleus are processed and transported to the cytoplasm, where they will be transported to the cytoplasmic domain. 2. Some mRNAs are translated to the proteins, which are transported to the cytoplasmic domain under the plasma membrane for packaging process. 3. Nucleic acids and proteins are transported to the plasma membrane domain, where the microvesicle formation will take place. The molecular cargo is sorted into the microvesicles through the molecular sorting machinery (e.g. ESCRT system). Enzymes and proteins e.g. ARF6 (ADP-ribosylation factor 6), PLD (Phospholipase D), ERK (Extracellular-signal regulated kinases) and MLCK (Myosin light-chain kinase) are responsible for the cell skeleton (mainly microfilament) organization. The floppase/flippase enzymes regulate the lipid domain content during the microvesicle formation process. 4. Microvesicles are secreted to the extracellular compartment. These membrane bound structures can travel through blood and lymphatic vessels, cerebrospinal fluid (CSF), saliva and other secretions of the body. Microvesicles possess adhesion and receptor proteins on their surfaces, which allows the microvesicles to bind to their specific targets.