title: Volume transmission and its different forms in the central nervous system.
abstract: Volume transmission (VT) is a widespread mode of intercellular communication that occurs in the extracellular fluid (ECF) and in the cerebrospinal fluid (CSF) of the brain with VT signals moving from source to target cells via energy gradients leading to diffusion and convection (flow). The VT channels are diffuse forming a plexus in the extracellular space, while in wiring transmission (WT) the channels (axons, terminals) are private. The speed is slow (seconds-minutes) in VT while rapid in the millisecond range in WT. The extracellular space is the substrate for VT, which is modulated by the extracellular matrix. Extrasynaptic VT is linked to synaptic transmission and likely often takes place due to incomplete diffusion barriers with the synaptic transmitter reaching extrasynaptic domains of the pre-and post-synaptic membrane of the synapse, the astroglia, and even adjacent synapses. Indications exist for the existence of striatal D2-like receptor-mediated extrasynaptic form of dopamine (DA) VT at the local circuit level in vivo in the human striatum. Synaptic glutamate via extrasynaptic VT can act on extrasynaptic metabotropic glutamate receptors located on the astroglia leading to Ca(2+) mediated astrocytic glutamate release into the extracellular space (ECS). Long distance peptide VT and CSF VT is the major long distance VT with distances more than 1 mm and flow in the CSF. Indications for long distance VT of beta-endorphin and oxytocin are obtained. We propose that monogamy in the female prairie vole may take place through an increase in oxytocin VT, especially in nucleus accumbens. Release of extracellular vesicles containing receptors, proteins, RNAs and mtDNA from cellular networks in the central nervous system (CNS) into the ECF and CSF may be a fundamental communication in the CNS. It represents a special form of volume transmission, the Roamer subtype of VT. It may greatly contribute to dynamic events of synaptic plasticity but also to spread of pathological proteins in protein conformational disorders. VT also occurs in the peripheral nervous system and associated cells. Short and long distance VT may take place in meridian channels via diffusion and flow in the interstitial fluid. Acupuncture can produce VT signals by releasing transmitters and modulators from nerve terminals and mast cells.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Kjell.Fuxe@ki.se
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.forename: Wilber
authors.initials: W
authors.lastname: Romero-Fernandez
authors.forename: Wei-Bo
authors.initials: WB
authors.lastname: Zhang
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Agnati
mesh_terms: D000818:Animals; D002450:Cell Communication; D002490:Central Nervous System / Q000166:cytology*; D005110:Extracellular Space / Q000378:metabolism*; D006801:Humans; D013569:Synapses / Q000378:metabolism