Krol K M, Crutcher K A, Kalisch B E, Rylett R J, Kawaja M D
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
J Comp Neurol. 2000 Nov 6;427(1):54-66. doi: 10.1002/1096-9861(20001106)427:1<54::aid-cne4>3.0.co;2-f.
Septal axons provide a cholinergic innervation to the nerve growth factor (NGF)-producing neurons of the mammalian hippocampus. These cholinergic septal afferents are capable of responding to target-derived NGF because they possess trkA and p75(NTR), the two transmembrane receptors that bind NGF and activate ligand-mediated intracellular signaling. To assess the relative importance of p75(NTR) expression for the responsiveness of cholinergic septal neurons to hippocampally derived NGF, we used three lines of mutant and/or transgenic mice: p75(-/-) mice (having two mutated alleles of the p75(NTR) gene), NGF/p75(+/+) mice (transgenic animals overexpressing NGF within central glial cells and having two normal alleles of the p75(NTR) gene), and NGF/p75(-/-) mice (NGF transgenic animals having two mutated alleles of the p75(NTR) gene). BALB/c and C57B1/6 mice (background strains for the mutant and transgenic lines of mice) were used as controls. Both lines of NGF transgenic mice possess elevated levels of NGF protein in the hippocampus and septal region, irrespective of p75(NTR) expression. BALB/c and C57Bl/6 mice display comparably lower levels of NGF protein in both tissues. Despite differing levels of NGF protein, the ratios of hippocampal to septal NGF levels are similar among BALB/c, C57B1/6, and NGF/p75(+/+) mice. Both p75(-/-) and NGF/p75(-/-) mice, on the other hand, have markedly elevated ratios of NGF protein between these two tissues. The lack of p75(NTR) expression also results in a pronounced absence of NGF immunoreactivity in cholinergic septal neurons of p75(-/-) and NGF/p75(-/-) mice. BALB/c, C57B1/6, and NGF/p75(+/+) mice, on the other hand, display NGF immunoreactivity that appears as discrete granules scattered through the cytoplasm of cholinergic septal neurons. Elevated levels of NGF in the hippocampus and septal region coincide with hypertrophy of cholinergic septal neurons of NGF/p75(+/+) mice but not of NGF/p75(-/-) mice. Levels of choline acetyltransferase (ChAT) enzyme activity are, however, elevated in the septal region and hippocampus of both NGF/p75(+/+) and NGF/p75(-/-) mice, compared with control mice. These data indicate that an absence of functional p75(NTR) expression disrupts the normal cellular immunolocalization of NGF by cholinergic septal neurons but does not affect the ability of these neurons to respond to elevated levels of NGF, as determined by ChAT activity.
隔区轴突为哺乳动物海马体中产生神经生长因子（NGF）的神经元提供胆碱能神经支配。这些胆碱能隔区传入神经能够对靶源性NGF作出反应，因为它们拥有trkA和p75（NTR），这两种跨膜受体可结合NGF并激活配体介导的细胞内信号传导。为了评估p75（NTR）表达对胆碱能隔区神经元对海马源性NGF反应性的相对重要性，我们使用了三系突变和/或转基因小鼠：p75（-/-）小鼠（具有p75（NTR）基因的两个突变等位基因）、NGF/p75（+/ +）小鼠（在中枢神经胶质细胞中过表达NGF且具有p75（NTR）基因的两个正常等位基因的转基因动物）和NGF/p75（-/-）小鼠（具有p75（NTR）基因的两个突变等位基因的NGF转基因动物）。BALB/c和C57B1/6小鼠（小鼠突变和转基因品系的背景品系）用作对照。两系NGF转基因小鼠在海马体和隔区中均具有升高的NGF蛋白水平，与p75（NTR）表达无关。BALB/c和C57Bl/6小鼠在这两个组织中的NGF蛋白水平相对较低。尽管NGF蛋白水平不同，但BALB/c、C57B1/6和NGF/p75（+/ +）小鼠海马体与隔区NGF水平的比率相似。另一方面，p75（-/-）和NGF/p75（-/-）小鼠在这两个组织之间的NGF蛋白比率明显升高。p75（NTR）表达的缺失还导致p75（-/-）和NGF/p75（-/-）小鼠胆碱能隔区神经元中NGF免疫反应性明显缺失。另一方面，BALB/c、C57B1/6和NGF/p75（+/ +）小鼠显示出NGF免疫反应性，表现为散布在胆碱能隔区神经元细胞质中的离散颗粒。海马体和隔区中NGF水平的升高与NGF/p75（+/ +）小鼠而非NGF/p75（-/-）小鼠胆碱能隔区神经元的肥大一致。然而，与对照小鼠相比，NGF/p75（+/ +）和NGF/p75（-/-）小鼠隔区和海马体中的胆碱乙酰转移酶（ChAT）酶活性水平均升高。这些数据表明，功能性p75（NTR）表达的缺失会破坏胆碱能隔区神经元对NGF的正常细胞免疫定位，但不影响这些神经元对升高的NGF水平作出反应的能力，这由ChAT活性确定。
