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

Abstract

One contribution of 16 to a discussion meeting issue 'Release of chemical transmitters from cell bodies and dendrites of nerve cells'. 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 extrasynaptic (short distance) and long distance (paraaxonal 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.

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…Homodimers are pairs of the same protomer, whereas heterodimers are formed from distinct GPCR. The number of described homodimers and heterodimers in both cellular systems and native tissues is at present very high (see Fuxe et al, 2015;Guidolin et al, 2015;Borroto-Escuela et al, 2017; Farran, 2017, for reviews), and Table 1 only provides some example. However, the evidence that a GPCR can exploit multiple interaction interfaces can significantly influence the architecture of the resulting receptor complexes in at least two aspects: -The first concerns the stoichiometry of the complex (i.e.…”

“…Furthermore, the system exhibited a limited number of equilibrium configurations or 'attractors', leading to the hypothesis that such a set of configurations could be interpreted as a form of information storage (engram) at the level of synapses and intercellular connections (Agnati et al, 1982Guidolin et al, 2007). Thus, the suitable reorganization of receptor complexes in the postsynaptic membrane has been recently proposed as the molecular basis of learning and memory (Fuxe et al, 2014b;Borroto-Escuela et al, 2015).…”

“…It has to be emphasized that the role played by RM in VMN is of particular importance from the pharmacologic point of view, as it discloses a marked rise of the repertoire of GPCR recognition and signaling Borroto-Escuela et al, 2017).…”

“…They can be briefly summarized as follows (see Guidolin et al, 2015;Borroto-Escuela et al, 2017;Farran, 2017, for more specific reviews): -Modulation of the binding sites has been reported to occur in a variety of RM as a consequence of allosteric RRI. One of the first examples was the A 2A -D 2 heterodimer, where the binding of the adenosine A 2A agonist CGS-21680 lead to a reduction of the affinity of the high-affinity dopamine D 2 agonist binding site (Fuxe et al, 1998).…”

“…This aspect is presently the subject of intense research (see Guidolin et al, 2015;Borroto-Escuela et al, 2017;Farran, 2017, for recent reviews). In recent years, such an effort allowed the characterization of a panel of receptor complexes representing possible targets for the treatment of pathologic conditions, such as Parkinson's disease , schizophrenia and depression Sahlholm et al, 2017), neuropathic pain , addiction (Gomes et al, 2013), and food intake disorders (Kern et al, 2012).…”