Learning and memory deficits in Notch mutant mice
Learning and memory deficits in Notch mutant mice
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DOI：
10.1016/s0960-9822(03)00492-5
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发表时间：
2003-08-05
期刊：
影响因子：
9.2
通讯作者：
Silva, AJ
中科院分区：
文献类型：
--
作者：
Costa, RM;Honjo, T;Silva, AJ
Notch是进化保守信号机制的重要组成部分，调控发育[1]，并可能参与可塑性相关过程，包括神经突结构[2]的改变和神经干细胞[3]的维持。Notch通路的缺陷导致Alagille[4]和Cadasil综合征[5]，这两种综合征与智力迟钝和痴呆有关。此外，在有丝分裂后神经元中，Notch蛋白与早老素相互作用[6-9]，与β -淀粉样蛋白前体蛋白[10]相互作用，因此可能在家族性和散发性阿尔茨海默病相关的记忆缺陷中发挥作用。为了测试Notch信号的改变是否会导致学习和记忆缺陷，我们研究了该通路突变的小鼠。在这里，我们发现Notch1的零杂合突变会导致空间学习和记忆的缺陷，而不会影响其他形式的学习、运动控制或探索活动。我们还发现，下游辅助因子RBP-J的零杂合突变会导致类似的特定空间学习和记忆缺陷。这些数据表明，Notch信号的组成性减少可导致特定的学习和记忆缺陷，并提示Notch依赖性转录的异常可能导致与阿尔茨海默病和Alagille和Cadasil综合征相关的认知缺陷。
Notch is a critical component of evolutionarily conserved signaling mechanisms that regulate development [1] and may contribute to plasticity-related processes, including changes in neurite structure [2] and maintenance of neural stem cells [3]. Deficits in the Notch pathway are responsible for Alagille [4] and Cadasil syndromes [5], which are associated with mental retardation and dementia. Additionally, in postmitotic neurons, Notch proteins interact with presenilins [6-9] and with beta-amyloid precursor protein [10] and could therefore have a role in the memory deficits associated with familial and sporadic Alzheimer's disease. To test if alterations in Notch signaling can lead to learning and memory deficits, we studied mice with mutations in this pathway. Here, we show that null heterozygous mutations in Notch1 result in deficits in spatial learning and memory without affecting other forms of learning, motor control, or exploratory activity. We also show that null heterozygous mutations in the downstream cofactor RBP-J result in similarly specific spatial learning and memory deficits. These data indicate that a constitutive decrease in Notch signaling can result in specific learning and memory deficits and suggest that abnormalities in Notch-dependent transcription may contribute to the cognitive deficits associated with Alzheimer's disease and Alagille and Cadasil syndromes.