Lindholm D, Carroll P, Tzimagiorgis G, Thoenen H
Department of Neurochemistry, Max Planck Institute for Psychiatry, Am Klopferspitz 18a, D-82152 Martinsried/ Munich, Germany.
Eur J Neurosci. 1996 Jul;8(7):1452-60. doi: 10.1111/j.1460-9568.1996.tb01607.x.
In contrast to sympathetic and sensory neurons in the peripheral nervous system, the neurotrophic requirements for neurons in the central nervous system (CNS) have not been clearly identified. The inactivation of specific neurotrophic factors and their receptors by gene targeting has shown that there are no major changes in neuron numbers in the CNS. This suggests an overlap between the action of different neurotrophic factors in the brain during development. Here we have studied the survival of hippocampal neurons prepared from embryonic rats using different culture conditions. Whereas the hippocampal neurons survive well in culture when plated at high density, they die at lower cell densities in the absence of appropriate neurotrophic factors. Under the latter conditions, both insulin-like growth factor-1 (IGF-1) and neurotrophins - brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) - rescued a large proportion of cultured neurons. In addition, hippocampal neurons from BDNF knockout mice exhibited enhanced cell death compared with cells from wild-type animals. BDNF and IGF-1 both increased the survival of the hippocampal neurons lacking BDNF, showing complementary action for these factors in supporting survival. Blocking antibodies against NT-3 and IGF-1 decreased hippocampal neuron survival at low cell densities, showing autocrine or paracrine action of the factors. At higher cell densities, however, the antibodies had no effect, demonstrating that there is a sufficient amount of endogenous factors in supporting survival. Blocking antibodies against NT-3 and IGF-1 decreased hippocampal neurons depend for survival on local neurotrophic factors such as IGF-1, BDNF and NT-3, which act in an autocrine/paracrine manner. The multifactorial support of hippocampal neurons ensures a maximal degree of neuron survival even in the absence of an individual factor
与外周神经系统中的交感神经元和感觉神经元不同，中枢神经系统（CNS）中神经元的神经营养需求尚未明确确定。通过基因靶向使特定神经营养因子及其受体失活的研究表明，中枢神经系统中神经元数量没有重大变化。这表明在发育过程中，大脑中不同神经营养因子的作用存在重叠。在此，我们使用不同的培养条件研究了从胚胎大鼠制备的海马神经元的存活情况。当以高密度接种时，海马神经元在培养中存活良好，但在缺乏适当神经营养因子的情况下，较低细胞密度时它们会死亡。在后一种条件下，胰岛素样生长因子-1（IGF-1）和神经营养因子——脑源性神经营养因子（BDNF）、神经营养因子-3（NT-3）和神经营养因子-4（NT-4）——挽救了很大一部分培养的神经元。此外，与野生型动物的细胞相比，BDNF基因敲除小鼠的海马神经元表现出增强的细胞死亡。BDNF和IGF-1都增加了缺乏BDNF的海马神经元的存活，表明这些因子在支持存活方面具有互补作用。针对NT-3和IGF-1的阻断抗体在低细胞密度下降低了海马神经元的存活，表明这些因子具有自分泌或旁分泌作用。然而，在较高细胞密度下，抗体没有作用，这表明存在足够量的内源性因子来支持存活。针对NT-3和IGF-1的阻断抗体降低了海马神经元的存活，说明海马神经元的存活依赖于局部神经营养因子，如IGF-1、BDNF和NT-3，它们以自分泌/旁分泌方式起作用。海马神经元的多因素支持确保即使在缺乏单个因子的情况下也能实现最大程度的神经元存活
