Department of Physiology, Neurobiology Unit, Center of Ageing and Regeneration (CARE), Nucleus Millennium in Regenerative Biology (MINREB), Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Alameda 340, CP 8331010, Santiago, Chile.
Mol Neurodegener. 2010 Jan 19;5:5. doi: 10.1186/1750-1326-5-5.
Septal cholinergic neurons account for most of the cholinergic innervations of the hippocampus, playing a key role in the regulation of hippocampal synaptic activity. Disruption of the septo-hippocampal pathway by an experimental transection of the fimbria-fornix drastically reduces the target-derived trophic support received by cholinergic septal neurons, mainly nerve growth factor (NGF) from the hippocampus. Axotomy of cholinergic neurons induces a reduction in the number of neurons positive for cholinergic markers in the medial septum. In several studies, the reduction of cholinergic markers has been interpreted as analogous to the neurodegeneration of cholinergic cells, ruling out the possibility that neurons lose their cholinergic phenotype without dying. Understanding the mechanism of cholinergic neurodegeneration after axotomy is relevant, since this paradigm has been extensively explored as an animal model of the cholinergic impairment observed in neuropathologies such as Alzheimer's disease.The principal aim of this study was to evaluate, using modern quantitative confocal microscopy, neurodegenerative changes in septal cholinergic neurons after axotomy and to assess their response to delayed infusion of NGF in rats.
We found that there is a slow reduction of cholinergic cells labeled by ChAT and p75 after axotomy. However, this phenomenon is not accompanied by neurodegenerative changes or by a decrease in total neuronal number in the medial septum. Although the remaining axotomized-neurons appear healthy, they are unable to respond to delayed NGF infusion.
Our results demonstrate that at 3 weeks, axotomized cholinergic neurons lose their cholinergic phenotype without dying and down-regulate their NGF-receptors, precluding the possibility of a response to NGF. Therefore, the physiological role of NGF in the adult septal cholinergic system is to support phenotypic differentiation and not survival of neurons. This evidence raises questions about the relationship between transcriptional regulation of the cholinergic phenotype by retrograde-derived trophic signaling and the transcriptional changes experienced when retrograde transport is impaired due to neuropathological conditions.
隔区胆碱能神经元构成了海马胆碱能神经支配的大部分，在调节海马突触活动方面发挥着关键作用。穹窿-海马伞的实验性横断破坏了隔海马通路，大大减少了胆碱能隔区神经元所接受的来自海马的靶源性营养支持，主要是神经生长因子（NGF）。胆碱能神经元的轴突切断导致内侧隔区胆碱能标志物阳性神经元的数量减少。在几项研究中，胆碱能标志物的减少被解释为类似于胆碱能细胞的神经退行性变，排除了神经元在不死亡的情况下失去其胆碱能表型的可能性。了解轴突切断后胆碱能神经退行性变的机制很重要，因为这种范式已被广泛探索作为神经病理学中观察到的胆碱能损伤的动物模型，如阿尔茨海默病。本研究的主要目的是使用现代定量共聚焦显微镜评估隔区胆碱能神经元轴突切断后的神经退行性变化，并评估它们对大鼠中 NGF 延迟输注的反应。
我们发现 ChAT 和 p75 标记的隔区胆碱能细胞在轴突切断后会缓慢减少。然而，这种现象并不伴有神经退行性变化或内侧隔区总神经元数量减少。尽管剩余的轴突切断神经元看起来健康，但它们无法对延迟的 NGF 输注作出反应。
我们的结果表明，在 3 周时，轴突切断的胆碱能神经元失去了它们的胆碱能表型而没有死亡，并下调了它们的 NGF 受体，排除了对 NGF 作出反应的可能性。因此，NGF 在成年隔区胆碱能系统中的生理作用是支持表型分化，而不是神经元的存活。这一证据引发了关于逆行源性营养信号对胆碱能表型的转录调控与由于神经病理学条件导致逆行转运受损时经历的转录变化之间关系的问题。
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