The balance and integration of different forms of volume and wiring transmission in the CNS. Relevance for schizophrenia

There is the existence of two main modes of intercellular communication in the Central Nervous System (CNS): the wiring transmission (WT), the prototype being synaptic transmission and the volume transmission (VT). A novel type of WT, the tunneling nanotube type may exist. VT uses the extracellular space (ECS) and the ventricular system as important channels for chemical transmission in the CNS complementary toWTwith diffusion and flow of transmitters, ions, trophic factors, etc. in the extracellular fluid (ECF) and cerebrospinal fluid (CSF). A short distance type (extrasynaptic transmission) and a long distance type of VT including the CSF type are found together with an extracellular vesicle mediated VT, called a roamer type of VT. Via the latter subtype several messages are sent via extracellular vesicles, mainly exosomes, containing selected mRNAs and miRNAs, proteins and lipids. They are released into the ECS and diffuse and flow until the proper targets are reached. The intrinsic features of exosomes allow their specific interaction with the appropriate target cells. They roam from cell to cell to disseminate important information but can also transfer pathologically altered proteins (e.g. toxic oligomers of amyloid beta and of alphasynuclein) contributing to spread of neurodegeneration. The balance and integration of synaptic and VT signals are achieved to a substantial degree via allosteric receptor– receptor interactions in GPCR-GPCR heteroreceptor complexes and especially ion-channel receptor-GPCR heteroreceptor complexes in the plasma membrane of synaptic and extrasynaptic regions. Disturbances in these receptor–receptor interactions by mild enkephalitis may contribute to development of schizophrenia, since many NMDA, GABA, D2 and 5-HT2A receptors are protomers in heteroreceptor complexes and are also known targets for antipsychotic drugs. The hypothesis is that in neuroinflammation glial microvesicles (extracellular vesicles) may be released which contain chemokine and cytokine receptors. The extracellular vesicles can be internalized into surrounding neurons via cell adhesion receptors. In view of the bioinformatic results obtained based on the triplet puzzle theory, immune receptors CXCR4, CCR2 and IL1R2 may form heteroreceptor complexes with neuronal NMDA, GABAA and GABAB receptors which involves the triplet homologies ITL, SVS, VST, GLL, LYS, and YSG. They appear to be part of the interface of these human heteroreceptor complexes built up of neural and immune receptor protomers. Through the allosteric receptor–receptor interactions in such postulated pathological heteroreceptor complexes the neuronal NMDA, GABAA and GABAB protomers may change their function in neuronal networks of the brain. This process can then contribute to positive, negative and/or cognitive symptoms of schizophrenia in line with the mild encephalitis hypothesis of schizophrenia. The glially derived kynurenines via VT participate in an important way in this integration of signals especially in the glutamate synapses and are altered in schizophrenia potentially related to mild neuroinflammation.