Extrasynaptic volume transmission is mediated by the diffusion of neuroactive substances in the extracellular space of the nervous system (ECS) and plays an important role in short- and long-distance communication between nerve cells. The ability of a substance to reach extrasynaptic high-affinity receptors via diffusion depends on the ECS diffusion parameters, i.e. the size of the ECS volume and the presence of diffusion barriers represented by, for example, fine astrocytic and neuronal processes or the extracellular matrix (ECM). In many brain regions such as the corpus callosum, hippocampus, cerebellum and supraoptic nucleus, these barriers may facilitate the diffusion of substances in the ECS in one direction rather than in another, thus the diffusion is anisotropic. Ionic changes and amino acid release evoke cell swelling, which leads to a concomitant decrease in ECS volume and also in the apparent diffusion coefficients of ions, neuroactive substances and water. Using ion-selective microelectrodes or diffusion-weighted MRI, changes in the ECS diffusion parameters have been found in many physiological and pathological states in which glial remodeling and ECM changes are among the key factors influencing diffusion. Thus, the movement of substances in the ECS is affected not only by the size of the pores between cells, but also by glial structure and ECM composition changes, which may significantly influence the diffusion of neuroactive substances, extrasynaptic transmission, neuron-glia communication, the "spillover" of mediators, synaptic "cross-talk", hormonal release and cell migration.

Supported by AVOZ 50390512 and LC554