Syková E, Mazel T, Simonová Z
Department of Neuroscience, Second Medical Faculty, Charles University, Prague, Czech Republic.
Exp Gerontol. 1998 Nov-Dec;33(7-8):837-51. doi: 10.1016/s0531-5565(98)00038-2.
Changes in brain extracellular space (ECS) volume, composition, and geometry are a consequence of neuronal activity, of glial K+, pH, and amino acid homeostasis, and of changes in glial cell morphology, proliferation, and function. They occur as a result of repetitive neuronal activity, seizures, anoxia, injury, inflammation, and many other pathological states in the CNS, and may significantly affect signal transmission in the CNS. Activity-related or CNS damage-related cellular swelling is compensated for by ECS volume shrinkage and, as a consequence, by a decrease in the apparent diffusion coefficients (ADCs) of neuroactive substances diffusing in the ECS. Changes in cellular morphology, such as occur during aging, could also result in changes of ECS volume and geometry. We provide evidence for limited diffusion in rat cortex, corpus callosum, and hippocampus in the aging brain that correlates with changes in glial volume and the extracellular matrix. In all structures, the mean ECS volume fraction alpha (alpha = ECS volume/total tissue volume) and nonspecific uptake k' are significantly lower in aged rats (26-32 months old) than in young adult brain. Compared to young adult brain, in the aged brain we found an increase in GFAP staining and hypertrophied astrocytes with thicker processes which, in the hippocampus, lost their radial organization. The tortuosity (lambda = square root of D/ADC) was lower in the cortex and CA3 region. Immunohistochemical staining for fibronectin and chondroitin sulfate proteoglycans revealed a substantial decrease that could account for a decrease in diffusion barriers. Diffusion parameters alpha, lambda, and k' in the aging brain after cardiac arrest changed substantially faster than in the young adult brain, although the final values were not significantly different. This suggests that the smaller extracellular space during aging results in a greater susceptibility of the aging brain to anoxia/ischemia, apparently due to a faster extracellular acidosis and accumulation of K+ and toxic substances, for example, glutamate. We conclude that during aging the movement of substances is more hindered in the narrower clefts. This is partly compensated for by a decrease in the diffusion barriers that may be formed by macromolecules of the extracellular matrix. Diffusion parameters can affect the efficacy of synaptic as well as extrasynaptic transmission by a greater accumulation of substances, because they diffuse away from a source more slowly, or induce damage to nerve cells if these substances reach toxic concentrations. Diffusion parameters are also of importance in the "crosstalk" between synapses, which has been hypothesized to be of importance during LTP and LTD. We can, therefore, assume that the observed changes in ECS diffusion parameters during aging can contribute to functional deficits and memory loss.
脑细胞外间隙（ECS）体积、组成和几何形状的变化是神经元活动、胶质细胞钾离子、pH值和氨基酸稳态以及胶质细胞形态、增殖和功能变化的结果。它们是由重复性神经元活动、癫痫发作、缺氧、损伤、炎症以及中枢神经系统中的许多其他病理状态引起的，并且可能显著影响中枢神经系统中的信号传递。与活动相关或与中枢神经系统损伤相关的细胞肿胀通过ECS体积缩小得到补偿，结果是，在ECS中扩散的神经活性物质的表观扩散系数（ADC）降低。细胞形态的变化，如在衰老过程中发生的变化，也可能导致ECS体积和几何形状的改变。我们提供了衰老大脑中大鼠皮质、胼胝体和海马体中有限扩散的证据，这与胶质细胞体积和细胞外基质的变化相关。在所有结构中，老年大鼠（26 - 32月龄）的平均ECS体积分数α（α = ECS体积/总组织体积）和非特异性摄取k'显著低于年轻成年大脑。与年轻成年大脑相比，在老年大脑中，我们发现胶质纤维酸性蛋白（GFAP）染色增加，星形胶质细胞肥大，其突起更厚，在海马体中，这些星形胶质细胞失去了其放射状排列。皮质和CA3区域的曲折度（λ = D/ADC的平方根）较低。纤连蛋白和硫酸软骨素蛋白聚糖的免疫组织化学染色显示显著减少，这可能解释了扩散屏障的减少。心脏骤停后衰老大脑中的扩散参数α、λ和k'的变化比年轻成年大脑中变化得更快，尽管最终值没有显著差异。这表明衰老过程中较小的细胞外间隙导致衰老大脑对缺氧/缺血更敏感，显然是由于更快的细胞外酸中毒以及钾离子和有毒物质（例如谷氨酸）的积累。我们得出结论，在衰老过程中，物质在更狭窄的间隙中移动受到更大阻碍。这部分通过细胞外基质大分子可能形成的扩散屏障的减少得到补偿。扩散参数可以通过物质的更大积累影响突触以及突触外传递的效率，因为它们从源扩散走的速度更慢，或者如果这些物质达到有毒浓度则诱导神经细胞损伤。扩散参数在突触之间的“串扰”中也很重要，据推测这在长时程增强（LTP）和长时程抑制（LTD）期间很重要。因此，我们可以假设在衰老过程中观察到的ECS扩散参数变化可能导致功能缺陷和记忆丧失。
