Montero C N, Hefti F
Department of Neurology, University of Miami Medical School, Florida 33101.
J Neurosci. 1988 Aug;8(8):2986-99. doi: 10.1523/JNEUROSCI.08-08-02986.1988.
We earlier reported that chronic intraventricular injections of NGF into adult rats with partial transection of the fimbria prevent the lesion-induced disappearance of cholinergic neurons in the medial septal nucleus and the diagonal band of Broca (Hefti, 1986). The present study assessed the specificity and treatment requirements of this effect of NGF. Immunohistochemical visualization of NGF receptors (NGF-R) revealed that these molecules are selectively located in forebrain cholinergic neurons of unlesioned brains. Fimbrial transection resulted in transient accumulation of NGF-R in proximal stumps of lesioned axons but failed to induce the expression of NGF-R by other cells in the septal area or near the lesion. Two to three weeks after lesioning, the number of septal neurons expressing NGF-R was reduced by approximately 50% in parallel with the reduction of the number of neurons expressing cholinergic marker enzymes. Repeated intraventricular NGF injections during 4 weeks prevented the disappearance of these cells. Fimbrial transections also reduced the number of septal GABAergic neurons visualized by glutamate decarboxylase immunohistochemistry. The loss of GABAergic neurons was not prevented by NGF. These findings suggest that NGF prevents the lesion-induced degeneration of cholinergic neurons by directly acting on NGF-R expressed by cholinergic cells and that NGF does not affect any neuron with an axonal lesion. Delayed start of the NGF treatment failed to prevent the disappearance of lesioned cholinergic neurons, providing evidence that NGF treatment indeed promotes the survival of these cells rather than simply upregulating the expression of transmitter-specific enzymes. A single injection of NGF at the time of the lesion was not sufficient to prevent the lesion-induced degeneration of cholinergic neurons. Furthermore, termination of chronic NGF treatment after 4 weeks was followed by loss of septal cholinergic neurons after an additional 4 weeks. These findings suggest that the continuous presence of NGF during more than 4 weeks is required to prevent the degeneration of cholinergic cells. The data are discussed in the context of a possible physiological role of NGF in the function of adult forebrain cholinergic neurons.
我们先前报道，向部分穹窿横断的成年大鼠脑室内长期注射神经生长因子（NGF），可防止损伤引起的内侧隔核和布罗卡斜带胆碱能神经元消失（赫夫蒂，1986年）。本研究评估了NGF这一作用的特异性和治疗条件。对NGF受体（NGF-R）进行免疫组化观察发现，这些分子选择性地位于未受损脑的前脑胆碱能神经元中。穹窿横断导致NGF-R在受损轴突的近端残端短暂积聚，但未能诱导隔区或损伤附近的其他细胞表达NGF-R。损伤后两到三周，表达NGF-R的隔区神经元数量减少了约50%，与此同时，表达胆碱能标记酶的神经元数量也减少。在4周内反复进行脑室内NGF注射可防止这些细胞消失。穹窿横断还减少了通过谷氨酸脱羧酶免疫组化观察到的隔区γ-氨基丁酸能神经元数量。NGF不能防止γ-氨基丁酸能神经元的丢失。这些发现表明，NGF通过直接作用于胆碱能细胞表达的NGF-R来防止损伤诱导的胆碱能神经元变性，并且NGF不会影响任何有轴突损伤的神经元。NGF治疗开始延迟未能防止受损胆碱能神经元消失，这证明NGF治疗确实促进了这些细胞的存活，而不仅仅是上调递质特异性酶的表达。在损伤时单次注射NGF不足以防止损伤诱导的胆碱能神经元变性。此外，在4周的慢性NGF治疗结束后，再过4周，隔区胆碱能神经元会丢失。这些发现表明，需要持续存在NGF超过4周才能防止胆碱能细胞变性。本文结合NGF在成年前脑胆碱能神经元功能中可能的生理作用对这些数据进行了讨论。
