Kater S B, Mattson M P, Guthrie P B
Department of Anatomy and Neurobiology, Colorado State University, Fort Collins 80523.
Ann N Y Acad Sci. 1989;568:252-61. doi: 10.1111/j.1749-6632.1989.tb12514.x.
The neuronal growth cone is involved in neurite elongation, directional pathfinding, and target recognition. These activities are essential for proper assembly of functional circuits within the developing nervous system, for regeneration of functional circuitry following damage, and also, perhaps, for remodeling of the nervous system in response to environmental stimuli. Our studies of both molluscan and mammalian neurons in culture have shown that neurite outgrowth can only proceed when intracellular calcium levels lie within a specific outgrowth-permissive range. Cessation of outgrowth can be induced by a variety of signals normally used for communication within the adult nervous system, including neurotransmitters, and action potentials; all of these signals elevate levels of intracellular calcium above the outgrowth-permissive range. For example, glutamate, whether added to the medium or released from co-cultured entorhinal explants, can selectively inhibit dendritic outgrowth. Conversely, inhibitory neurotransmitters can block the outgrowth-inhibitory effects of glutamate and actually promote expansion of dendritic arbors. Dendritic outgrowth is therefore regulated by a balance between excitatory and inhibitory neurotransmitter activity. Extreme excitatory imbalance in neurotransmitter input to pyramidal neurons causes cell death. Each of these changes in neuroarchitecture is mediated by changes in levels of intracellular calcium. We therefore put forward the hypothesis that key mechanisms which normally control the development and plasticity of neural circuitry, are also involved in neurodegeneration. Local, moderate elevations in calcium result in dendritic pruning. Higher, global elevations in calcium result in cell death. This cell death may serve an important function during normal development; aging may result in the same mechanism being employed pathologically. When intracellular calcium levels are not regulated within normal limits, as may occur in aging, neurodegeneration may occur.
神经元生长锥参与神经突伸长、定向路径寻找和靶标识别。这些活动对于发育中的神经系统内功能回路的正确组装、损伤后功能回路的再生，以及或许对于响应环境刺激的神经系统重塑至关重要。我们对培养的软体动物和哺乳动物神经元的研究表明，只有当细胞内钙水平处于特定的允许生长范围内时，神经突生长才能进行。生长的停止可由通常用于成年神经系统内通讯的多种信号诱导，包括神经递质和动作电位；所有这些信号都会使细胞内钙水平升高到允许生长范围之上。例如，谷氨酸，无论是添加到培养基中还是从共培养的内嗅外植体中释放出来，都可以选择性地抑制树突生长。相反，抑制性神经递质可以阻断谷氨酸的生长抑制作用，并实际上促进树突分支的扩展。因此，树突生长受兴奋性和抑制性神经递质活性之间平衡的调节。向锥体神经元输入神经递质时的极端兴奋性失衡会导致细胞死亡。神经结构的每一种变化都是由细胞内钙水平的变化介导的。因此，我们提出假说，即通常控制神经回路发育和可塑性的关键机制也参与神经退行性变。局部适度的钙升高导致树突修剪。更高的、全局性的钙升高导致细胞死亡。这种细胞死亡在正常发育过程中可能起重要作用；衰老可能导致相同的机制在病理情况下被采用。当细胞内钙水平不在正常范围内调节时，如在衰老过程中可能发生的那样，可能会发生神经退行性变。
