Changes in extracellular space (ECS) composition and geometry are a consequence of neuronal activity and of glial K+, pH, and amino acids homeostasis. They accompany the phenomena of repetitive neuronal activity and also occur as a result of seizures, anoxia, injury, and many other pathological states in the CNS, and they may significantly affect signal transmission in the CNS. Activity-related, or CNS damage-related ionic changes and release of amino acids result in fast, pulsatile, and long-term cellular (particularly glial) swelling. Cellular swelling is compensated for by ECS volume shrinkage and by a decrease in the apparent diffusion coefficients of neuroactive substances diffusing in the ECS. Movement of substances is hindered in the narrower clefts, but presumably also because of the crowding of molecules of the ECS matrix and/or by the swelling of the fine glial processes that form diffusional barriers. This can either increase efficacy of synaptic and nonsynaptic transmission by greater accumulation of substances or induce damage to nerve cells if these substances reach toxic concentrations.