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 changes in single or several strands of amino acids. It is of substantial interest to understand the role of altered receptor–receptor interactions as a mechanism for how neuroinflammatory processes can contribute to mental dysfunctions. It is hypothesized that chemokine and cytokine receptors may directly form heteroreceptor complexes with neuronal receptors known to be dysfunctional in schizophrenia and targets for antipsychotic drugs. Based on the current bioinformatic analysis performed we can postulate that chemokine receptor CXCR4 may directly interact with GABAB2 and NR2A subunits of the NMDAR, chemokine receptor CCR2 with NMDAR, GABAB1 subunit and GABAAR and cytokine receptor IL1R2 with GABAB1 subunit and NMDAR, all known to be involved in schizophrenia. Through the allosteric receptor–receptor interactions in such pathological heteroreceptor complexes the neuronal NMDA, GABAA and ABAB protomers may change their function (moonlighting) in neuronal networks of the brain. This process in neuroinflammation can contribute to positive, negative and/or cognitive symptoms of schizophrenia in line with the mild encephalitis hypothesis of schizophrenia. Neuroinflammation in schizophrenia may also disturb the integrative process of synaptic and volume transmission signals in glutamate synapses by altering kynurenines in the mammalian brain.