Extracellular fluids and glial cells are a significant proportion of the mammalian brain volume, and together constitute the local environment of the neurons. This environment is not static, but may undergo large alterations of size and chemical content during various stages of neuronal activity and pathology. Such changes may in turn have effects on neural activity. The anatomy and chemistry of the neuronal environment appear to change dramatically during postnatal development of the neocortex, but there is very little quantitative information regarding the extent of these changes, or the consequences for neuronal function during maturation. The proposed investigation will utilize in vitro brain slice techniques, ion-sensitive microelectrodes and intra- and extracellular recording to assess the phsiological state of the neuronal environment during the development of rat neocortex. Specifically, we will measure the volume fraction and tortuosity of the extracellular fluid and the diffusion of ions through these fluids. Since astrocytes proliferate and mature primarly during the postnatal period, we will test several predictions based on their physiological properties in the mature brain: extracellular slow potentials induced by increases in extracellular [K+] should increase with age; the diffusion of K+ relative to large impermeant cations, should increase with age; and activity- and K+ related decreases in the size of the extracellular space should become more prominent with age. Variations in extracellular K+ and Ca2+ activities will be measured under different modes of stimulation. Finally, the sensitivity of neuronal excitability to alterations in extracellular [K+] will be assessed in developing and mature neocortex. These studies will provide unique insight into the relationships between neuronal activity and the brain microenvironment, and should provide functional correlates of the anatomical and biochemical evidence already available for developing neocortex. The results will help to explain the cause and consequences of large ionic fluctuations seen during epileptic seizures, and the developmental study of glial function may have relevance to the mechanisms of cerebral edema.
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