Abstract
Extrasynaptic communication between neurons or neurons and glia is mediated by the diffusion of neuroactive substances in the extracellular space (ECS). Diffusion in the central nervous system (CNS) is inhomogeneous and often anisotropic.
Changes in ECS volume and geometry accompany physiological neuronal activity, development, lactation, stimulation, and aging, as well as pathological states, e.g., anoxia/ischemia, seizures, injury, demyelination, and tumors. Ionic changes and amino acid release result in cellular swelling, compensated for by ECS shrinkage and a decrease in the apparent diffusion coefficients of neuroactive substances or water (ADC(W)) as determined by diffusion analysis using the real-time iontophoretic tetramethylammonium (TMA(+)) method or diffusion-weighted NMR.
The diffusion parameters of the CNS in adult mammals (including humans), ECS volume fraction alpha (alpha = ECS volume/total tissue volume) 0.20-0.25 and tortuosity 1.5-1.6, hinder the diffusion of neuroactive substances and water. A significant decrease in ECS volume (to 0.16) and an increase in diffusion barriers (tortuosity), accompanied by learning deficits, occur in aging CNS, accompanied by astrogliosis, rearrangement of astrocytic processes, and a loss of extracellular matrix.
Decreases in ADC(TMA) and ADC(W) due to astrogliosis and increased proteoglycan expression were found after brain injury and in grafts of embryonic tissue. Tenascin-R-deficient mice also revealed significant changes in ADC(TMA) and ADC(W).
Plastic changes in ECS volume, tortuosity, and anisotropy significantly affect neuron-glia communication, the spatial relation of glial processes towards synapses, glutamate or GABA "spillover", and synaptic cross-talk. The various changes occur during pathological states and, as such, can be important for diagnosis, drug delivery, and treatment.