Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down's syndrome
Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down's syndrome
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DOI：
10.1006/exnr.1999.7289
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发表时间：
2000-02-01
影响因子：
5.3
通讯作者：
Crnic, LS
中科院分区：
文献类型：
--
作者：
Granholm, ACE;Sanders, LA;Crnic, LS
16号染色体节段性三体小鼠(Ts65Dn)已被用作唐氏综合征的模型，这些小鼠出生时基底前脑胆碱能神经元密度正常，但像唐氏综合征患者一样，这些神经元在以后的生活中经历了显著的退化。胆碱能神经元这种退化的时间进程尚未被研究，也不知道它是否与所描述的渐进性记忆和学习缺陷有关。4、6、8和10月龄Ts65Dn小鼠被处死以评估基底前脑的形态，不同组的小鼠分别进行视觉或空间辨别学习和翻转测试，我们发现4月龄Ts65Dn小鼠的胆碱能标记物没有变化，但此后胆碱能神经元密度逐渐下降，表现为胞体显著缩小。在所有时间点都观察到高亲和力神经生长因子受体TrkA的平行染色丢失，这表明该细胞存在生物学机制。涉及这一增长因素的损失。除短暂性学习任务要求困难外，三体小鼠在视觉辨别学习和反转方面没有损害，而空间学习和反转表现出显著的缺陷，特别是在6月龄以上的小鼠。因此，基底前脑中ChAT免疫反应神经元的丧失与在6个月大左右第一次发生的空间任务的行为灵活性缺陷相结合。提示Ts65Dn小鼠基底前脑胆碱能功能丧失和TrkA免疫反应性降低可能与认知功能障碍直接相关。(C)2000年学术出版社。
Mice with segmental trisomy of chromosome 16 (Ts65Dn) have been used as a model for Down's syndrome, These mice are born with a normal density of basal forebrain cholinergic neurons but, like patients with Down's syndrome, undergo a significant deterioration of these neurons later in life. The time course for this degeneration of cholinergic neurons has not been studied, nor is it known if it correlates with the progressive memory and learning deficits described. Ts65Dn mice that were 4, 6, 8, and 10 months old were sacrificed for evaluation of basal forebrain morphology, Separate groups of mice were tested on visual or spatial discrimination learning and reversal, We found no alterations in cholinergic markers in 4-month-old Ts65Dn mice, but thereafter a progressive decline in density of cholinergic neurons, as web as significant shrinkage of cell body size, was seen. A parallel loss of staining for the high-affinity nerve growth factor receptor, trkA, was observed at all time points, suggesting a biological mechanism for the cell. loss involving this growth factor. Other than transient difficulty in learning the task requirements, there was no impairment of trisomic mice on visual discrimination learning and reversal, whereas spatial learning and reversal showed significant deficits, particularly in the mice over 6 months of age. Thus, the loss of ChAT-immunoreactive neurons in the basal forebrain was coupled with simultaneous deficits in behavioral flexibility on a spatial task occurring for the first time around 6 months of age. These findings suggest that the loss of cholinergic function and the simultaneous decrease in trkA immunoreactivity in basal forebrain may directly correlate with cognitive impairment in the Ts65Dn mouse. (C) 2000 Academic Press.