Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase
Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase
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DOI：
10.1523/jneurosci.5566-05.2006
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发表时间：
2006-04-12
影响因子：
5.3
通讯作者：
Klann, E
中科院分区：
文献类型：
--
作者：
Hu, DY;Serrano, F;Klann, E
由活性氧（ROS）引起的氧化损伤已被认为与衰老的几种病理表现（包括认知功能障碍）密切相关。ROS，包括超氧化物，通常被认为是神经毒性分子，其作用可以通过抗氧化酶来减轻。然而，ROS也被认为是正常突触可塑性的信号转导级联的必要组成部分。因此，我们推断ROS和抗氧化酶在调节神经元过程中的作用在动物的一生中是不同的。我们研究了海马长时程增强（LTP）和记忆相关的行为表现在转基因小鼠过表达细胞外超氧化物歧化酶（EC-SOD）和野生型的同窝出生在不同的年龄。我们发现，老年EC-SOD转基因小鼠表现出增强海马LTP，更好的小脑依赖的运动学习，以及更好的海马依赖的空间学习与野生型同窝。我们还发现，EC-SOD过表达损害的背景学习，但在老年转基因小鼠的损害减少。在分子水平上，与老年野生型小鼠相比，老年EC-SOD转基因小鼠的超氧化物水平较低，蛋白质羰基水平降低，p38和细胞外信号调节激酶2磷酸化水平降低。我们的研究结果表明，超氧化物水平的升高有助于海马LTP和记忆中的衰老相关的损害，这些损害可以通过EC-SOD的过度表达来缓解。我们的结论是，有一个年龄依赖性的超氧化物在调节突触可塑性和学习记忆的作用改变。
Oxidative damage caused by reactive oxygen species (ROS) has been proposed to be critically involved in several pathological manifestations of aging, including cognitive dysfunction. ROS, including superoxide, are generally considered as neurotoxic molecules whose effects can be alleviated by antioxidant enzymes. However, ROS also are known to be necessary components of the signal transduction cascades underlying normal synaptic plasticity. Therefore, we reasoned that the role that ROS and antioxidant enzymes play in modulating neuronal processes varies over the lifespan of an animal. We examined hippocampal long-term potentiation (LTP) and memory-related behavioral performance in transgenic mice overexpressing extracellular superoxide dismutase (EC-SOD) and their wild-type littermates at different ages. We found that aged EC-SOD transgenic mice exhibited enhanced hippocampal LTP, better cerebellum-dependent motor learning, and better hippocampus-dependent spatial learning compared with their wild-type littermates. We also found that EC-SOD overexpression impaired contextual learning, but the impairment was decreased in the aged transgenic mice. At the molecular level, aged EC-SOD transgenic mice had lower superoxide levels, a decrease in protein carbonyl levels, and a decrease in p38 and extracellular signal-regulated kinase 2 phosphorylation compared with aged wild-type mice. Our findings suggest that elevated levels of superoxide contribute to aging-related impairments in hippocampal LTP and memory, and that these impairments can be alleviated by overexpression of EC-SOD. We conclude that there is an age-dependent alteration in the role of superoxide in modulating synaptic plasticity and learning and memory.