Understanding the balance and integration of volume and synaptic transmission. Relevance for psychiatry

The major difference of synaptic transmission vs volume transmission (VT) is about the channels which are private in synaptic transmission (axons and terminals) but diffuse in VT represented by the channel plexus of the extracellular space and the CSF. There exist different forms of VT: extrasynatic, long distance, CSF and roamer type VT, the last one mediated via microvesicles (extracellular vesicles). Interleukin-1b (IL-1b) may produce inflammation and sickness behavior via long distance and CSF VT. The balance and integration of VT and synaptic transmission through receptor–receptor interactions in heteroreceptor complexes appears crucial for CNS communication and of high relevance for psychiatric diseases like schizophrenia, depression, cocaine addiction and anxiety. The allosteric receptor–receptor mechanism causes a marked rise of the repertoire of GPCR recognition, pharmacology, trafficking and signaling of the participating receptor protomers. We have introduced the moonlighting concept into the GPCR heteromer field, since GPCR protomers can change their function through the allosteric receptor–receptor interactions. This is achieved through changes in recognition, G protein selectivity, and signaling via other proteins involving, e.g., a switch from G proteins to b-arrestin through conformational