Disruption of a Single Allele of the Nerve Growth Factor Gene Results in Atrophy of Basal Forebrain Cholinergic Neurons and Memory Deficits
Disruption of a Single Allele of the Nerve Growth Factor Gene Results in Atrophy of Basal Forebrain Cholinergic Neurons and Memory Deficits
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DOI：
10.1523/jneurosci.17-19-07288.1997
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发表时间：
1997-10
期刊：
影响因子：
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通讯作者：
Karen S. Chen;Merry C. Nishimura;M. Armanini;C. Crowley;S. Spencer;H. Phillips
中科院分区：
文献类型：
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作者：
Karen S. Chen;Merry C. Nishimura;M. Armanini;C. Crowley;S. Spencer;H. Phillips
神经生长因子（NGF）的管理，以老年或病变的动物已被证明可以扭转基底前脑胆碱能神经元的萎缩，并改善行为缺陷。为了研究内源性神经生长因子在基底前脑胆碱能细胞的存活和空间记忆中的重要性，研究了在神经生长因子基因的一个等位基因中具有破坏突变的小鼠。杂合突变小鼠（ngf+/−）海马内的NGF mRNA和蛋白水平降低，并且在Morris水迷宫中发现在记忆获得和保持方面表现出显着缺陷。在神经生长因子缺陷小鼠中观察到的行为缺陷伴随着表达胆碱能标记物的隔细胞的收缩和损失以及海马胆碱能神经支配的减少。将NGF注入成年NGF +/-小鼠的侧脑室消除了水迷宫任务的缺陷。可能需要长时间暴露于NGF以诱导认知效应，因为在长时间（5周）而非短时间（3天）输注后观察到获得缺陷的逆转。虽然神经生长因子管理没有导致任何改善的间隔细胞标记胆碱乙酰转移酶的数量，这种治疗有效地纠正了胆碱能神经元的大小和密度的海马胆碱能神经支配的赤字。这些研究结果表明，内源性神经生长因子的基底前脑胆碱能神经元的生存和功能的重要性，并揭示，部分耗尽这种营养因子与可测量的学习和记忆缺陷。
Administration of nerve growth factor (NGF) to aged or lesioned animals has been shown to reverse the atrophy of basal forebrain cholinergic neurons and ameliorate behavioral deficits. To examine the importance of endogenous NGF in the survival of basal forebrain cholinergic cells and in spatial memory, mice bearing a disruption mutation in one allele of the NGF gene were studied. Heterozygous mutant mice (ngf+/−) have reduced levels of NGF mRNA and protein within the hippocampus and were found to display significant deficits in memory acquisition and retention in the Morris water maze. The behavioral deficits observed in NGF-deficient mice were accompanied by both shrinkage and loss of septal cells expressing cholinergic markers and by a decrease in cholinergic innervation of the hippocampus. Infusions of NGF into the lateral ventricle of adultngf+/− mice abolished the deficits on the water maze task. Prolonged exposure to NGF may be required to induce cognitive effects, because reversal of the acquisition deficit was seen after long (5 weeks) but not short (3 d) infusion. Although NGF administration did not result in any improvement in the number of septal cells labeled for choline acetyltransferase, this treatment did effectively correct the deficits in both size of cholinergic neurons and density of cholinergic innervation of the hippocampus. These findings demonstrate the importance of endogenous NGF for survival and function of basal forebrain cholinergic neurons and reveal that partial depletion of this trophic factor is associated with measurable deficits in learning and memory.