The Neural Network and the role of Extracellular Vesicle Transfer

The proposal on the existence of two main modes of intercellular communication in the central nervous system (CNS) was introduced in 1986 and called wiring transmission (WT) and volume transmission (VT). The major criterion for this classification was the different characteristics of the communication channels with physical boundaries well delimited in the case of WT (axons and their synapses; gap junctions) but not in the case of VT (the extracellular fluid-filled tortuous channels of the extracellular space and the cerebrospinal fluid-filled ventricular space and subarachnoidal space). Recently, the Roamer type of VT (a subclass of VT) has been introduced based on the release by source cells of microvesicles (MV) containing proteins, mtDNA and RNA. Such safe vesicular carriers flow in the extracellular fluid along energy gradients from the source to target cells. Western blot, TEM and gene expression analyses demonstrate that MVs can transport GPCRs, suggesting the MV involvement in cell-to-cell communication. In order to further demonstrate that GPCRs can be exchanged among cells by means of MVs, we created two populations of cells, the first transfected with D2R-CFP and the second with A2AR-YFP. These two types of cells were co-cultured, and acceptor photobleaching FRET analysis demonstrated cells positive to both D2R-CFP and A2AR-YFP. Furthermore, recipient cells preincubated for 24 h with A2AR positive MVs were treated with the adenosine A2A receptor agonist CGS-21680. The significant increase in cAMP accumulation clearly demonstrated that A2ARs were functionally competent in target cells. These findings demonstrate that A2A receptors capable of recognizing and decoding extracellular signals can be safely transferred via MVs from source to target cells. The possibility of pharmacological interventions on composition and/or release of microvesicles (i.e., the Roamer type of VT) should be considered as new therapeutic approaches capable of modulating the decoding capabilities of neurons and/or glial cells.