Diffusion constraints and neuron-glia interaction during aging

Changes in brain extracellular space (ECS) volume, composition, and geometr y are a consequence of neuronal activity, of glial K+, pH, and amino acid h omeostasis, and of changes in glial cell morphology, proliferation, and fun ction. They occur as a result of repetitive neuronal activity, seizures, an oxia, injury, inflammation, and many other pathological states in the CNS, and may significantly affect signal transmission in the CNS. Activity-relat ed or CNS damage-related cellular swelling is compensated for by ECS volume shrinkage and, as a consequence, by a decrease in the apparent diffusion c oefficients (ADCs) of neuroactive substances diffusing in the ECS. Changes in cellular morphology, such as occur during aging, could also result in ch anges of ECS volume and geometry. We provide evidence for limited diffusion in rat cortex, corpus callosum, and hippocampus in the aging brain that co rrelates with changes in glial volume and the extracellular matrix. In all structures, the mean ECS volume fraction alpha (alpha = ECS volume/total ti ssue volume) and nonspecific uptake k' are significantly lower in aged rats (26-32 months old) than in young adult brain. Compared to young adult brai n, in the aged brain we found an increase in GFAP staining and hypertrophie d astrocytes with thicker processes which, in the hippocampus, lost their r adial organization. The tortuosity (lambda = root DIADC) was lower in the c ortex and CA3 region. Immunohistochemical staining for fibronectin and chon droitin sulfate proteoglycans revealed a substantial decrease that could ac count for a decrease in diffusion barriers. Diffusion parameters alpha, lam bda, and k' in the aging brain after cardiac arrest changed substantially f aster than in the young adult brain, although the final values were not sig nificantly different. This suggests that the smaller extracellular space du ring aging results in a greater susceptibility of the aging brain to anoxia /ischemia, apparently due to a faster extracellular acidosis and accumulati on of K+ and toxic substances, for example, glutamate. We conclude that dur ing aging the movement of substances is more hindered in the narrower cleft s. This is partly compensated for by a decrease in the diffusion barriers t hat may be formed by macromolecules of the extracellular matrix. Diffusion parameters can affect the efficacy of synaptic as well as extrasynaptic tra nsmission by a greater accumulation of substances, because they diffuse awa y from a source more slowly, or induce damage to nerve cells if these subst ances reach toxic concentrations. Diffusion parameters are also of importan ce in the "crosstalk" between synapses, which has been hypothesized to be o f importance during LTP and LTD. We can, therefore, assume that the observe d changes in ECS diffusion parameters during aging can contribute to functi onal deficits and memory loss. (C) 1998 Elsevier Science Inc.