Mattson M P, Dou P, Kater S B
Department of Anatomy and Neurobiology, Colorado State University, Fort Collins 80523.
J Neurosci. 1988 Jun;8(6):2087-100. doi: 10.1523/JNEUROSCI.08-06-02087.1988.
The present study examined the effects of glutamate on the outgrowth of dendrites and axons in isolated hippocampal pyramidal-like neurons in cell culture. During the first day of culture the survival and outgrowth of these neurons was unaffected by high concentrations (up to 1 nM) of glutamate, quisqualic acid (QA), kainic acid (KA), and N-methyl-D-aspartic acid. Beginning on day 2 of culture high levels of glutamate, KA and QA were toxic to the majority of pyramidal neurons, while subtoxic levels of these agents caused a well-defined, dose-dependent, sequence of effects on dendritic outgrowth. At increasing concentrations of glutamate, QA, and KA, the following events were observed: (1) dendritic outgrowth rates were reduced, while axonal elongation rates were unaffected; (2) dendritic length was reduced, while axons continued to grow; (3) dendrites regressed dramatically, and axonal outgrowth rate was reduced. These dendrite-specific effects of glutamate were apparently mediated at the growth cones since focal application of glutamate to individual dendritic growth cones resulted in suppression of growth cone activity and a regression of the dendrite; axons were unaffected by focal glutamate application. Pharmacological tests using glutamate receptor agonists and antagonists demonstrated that receptors of the KA/QA type mediated the glutamate effects on outgrowth and survival. The calcium channel blocker Co2+ prevented both glutamate neurotoxicity and glutamate-induced dendritic regression. Ionophore A23187 and elevations in extracellular K+ levels each caused a dose-dependent series of outgrowth and survival responses similar to those caused by glutamate. Taken together, these results indicate that activation of glutamate receptors leads to the opening of voltage-dependent calcium channels; the resulting increases in calcium influx lead to the observed alterations in dendritic outgrowth and neuronal survival.
本研究检测了谷氨酸对细胞培养中分离的海马锥体细胞样神经元树突和轴突生长的影响。在培养的第一天，这些神经元的存活和生长不受高浓度（高达1 nM）谷氨酸、quisqualic酸（QA）、海人酸（KA）和N-甲基-D-天冬氨酸的影响。从培养的第二天开始，高浓度的谷氨酸、KA和QA对大多数锥体神经元有毒性，而这些药物的亚毒性水平对树突生长产生明确的、剂量依赖性的一系列影响。随着谷氨酸、QA和KA浓度的增加，观察到以下事件：（1）树突生长速率降低，而轴突伸长速率不受影响；（2）树突长度缩短，而轴突继续生长；（3）树突显著退化，轴突生长速率降低。谷氨酸对树突的这些特异性作用显然是在生长锥处介导的，因为将谷氨酸局部应用于单个树突生长锥会导致生长锥活性受到抑制和树突退化；轴突不受局部谷氨酸应用的影响。使用谷氨酸受体激动剂和拮抗剂的药理学试验表明，KA/QA型受体介导了谷氨酸对生长和存活的影响。钙通道阻滞剂Co2+可预防谷氨酸神经毒性和谷氨酸诱导的树突退化。离子载体A23187和细胞外K+水平升高均引起一系列剂量依赖性的生长和存活反应，类似于谷氨酸引起的反应。综上所述，这些结果表明谷氨酸受体的激活导致电压依赖性钙通道开放；由此导致的钙内流增加导致观察到的树突生长和神经元存活的改变。
