The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural-glial networks

Two major types of intercellular communication are found in the central nervous system (CNS), namely wiring transmission (point-to-point communication, the prototype being synaptic transmission with axons and terminals) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid (CSF)) involving large numbers of cells in the CNS. Volume and synaptic transmission become integrated inter alia through the ability of their chemical signals to activate different types of receptor protomers in heteroreceptor complexes located synaptically or extrasynaptically in the plasma membrane. The demonstration of extracellular dopamine (DA) and serotonin (5-HT) fluorescence around the DA and 5-HT nerve cell bodies with the Falck-Hillarp formaldehyde fluorescence method after treatment with amphetamine and chlorimipramine, respectively, gave the first indications of the existence of VT in the brain, at least at the soma level. There exist different forms of VT. Early studies on VT only involved spread including diffusion and flow of soluble biological signals, especially transmitters and modulators, a communication called extra synaptic (short distance) and long distance (para-axonal and paravascular and CSF pathways) VT. Also, the extracellular vesicle type of VT was demonstrated. The exosomes (endosome-derived vesicles) appear to be the major vesicular carriers for VT but the larger microvesicles also participate. Both mainly originate at the soma-dendritic level. They can transfer lipids and proteins, including receptors, Rab GTPases, tetraspanins, cholesterol, sphingolipids and ceramide. Within them there are also subsets of mRNAs and non-coding regulatory microRNAs. At the soma-dendritic membrane, sets of dynamic postsynaptic heteroreceptor complexes (built up of different types of physically interacting receptors and proteins) involving inter alia G protein-coupled receptors including autoreceptors, ion channel receptors and receptor tyrosine kinases are hypothesized to be the molecular basis for learning and memory. At nerve terminals, the presynaptic heteroreceptor complexes are postulated to undergo plastic changes to maintain the pattern of multiple transmitter release reflecting the firing pattern to be learned by the heteroreceptor complexes in the postsynaptic membrane.