Although synaptic transmission is an important means of communication between neurons themselves, neurons and glia also communicate by extrasynaptic "volume" transmission, which is mediated by diffusion in the extracellular space (ECS). The ECS of the central nervous system (CNS) is the microenvironment of neurons and glial cells. The composition and size of the ECS changes dynamically during neuronal activity as well as during pathological states. Following their release, a number of neuroactive substances, including ions, mediators, metabolites and neurotransmitters, diffuse via the ECS to targets distant from their release sites. Glial cells affect the composition and volume of the ECS and therefore also extracellular diffusion, particularly during development, aging and pathological states such as ischemia, injury, X-irradiation, gliosis, Alzheimer´s disease, demyelination diseases, epilepsy and tumors. A decrease in ECS volume and an increase in diffusion barriers were found during ageing in the rat and mouse cortex, corpus callosum and hippocampus. These changes were accompanied by a learning deficit, astrogliosis, the rearrangement of astrocytic processes and a loss of extracellular matrix (ECM). An increase in diffusion barriers, manifested also as a decrease in the apparent diffusion coefficient (ADC), due to astrogliosis as well as due to an increase in chondroitin sulphate proteoglycans was also found after cortical injury and in grafts of embryonic tissue. Measurements in mice deficient for the ECM glycoprotein Tenascin-R revealed not only an increase in ADCs, but also a smaller ECS volume fraction, while APP23 mice with excessive amyloid plaque deposition had a larger ECS volume fraction. Similarly in tumors where we found a large increase in ESC volume, ADCs are decreased due to the large deposition of ECM. The ECM, besides its apparent importance in tissue anisotropy, is therefore important for maintaining a relatively large ECS volume (Sykova and Nicholson, Physiol. Rev., 2008).

Supported by the Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, and the Center for Neuroscience, Prague, Czech Republic.