The M-Current Inhibitor XE991 Decreases the Stimulation Threshold for Long-Term Synaptic Plasticity in Healthy Mice and in Models of Cognitive Disease
The M-Current Inhibitor XE991 Decreases the Stimulation Threshold for Long-Term Synaptic Plasticity in Healthy Mice and in Models of Cognitive Disease
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DOI：
10.1002/hipo.20717
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发表时间：
2011-01-01
期刊：
影响因子：
3.5
通讯作者：
Manuel Carrion, Angel
中科院分区：
文献类型：
--
作者：
Fontan-Lozano, Angela;Suarez-Pereira, Irene;Manuel Carrion, Angel
衰老、智力迟钝、精神和神经系统疾病的数量都与学习和记忆障碍有关。由于这些疾病的根本原因是非常异质的，可以在不同情况下增强小鼠学习和记忆的操作可能能够克服患者的认知缺陷。M电流调节神经元兴奋性和动作电位放电，表明其抑制可能会增加认知能力。我们证明，XE991，一个特定的M-电流阻断剂，增强健康小鼠的学习和记忆。这种效应可能是通过改变基础海马突触活动和减少突触功效和学习相关基因表达长期变化的刺激阈值来实现的。我们还表明，训练课程调节M-电流通过瞬时降低KCNQ/Kv7.3蛋白的水平，一个关键的亚基的M-电流。此外，我们发现XE991可以逆转与乙酰胆碱耗竭相关的认知障碍和海人酸诱导的神经变性。总之，这些结果表明，抑制M电流作为一种通用策略可能有助于增强健康和老龄化个体以及神经退行性疾病患者的认知能力。(C)2009威利-利斯公司
Aging, mental retardation, number of psychiatric and neurological disorders are all associated with learning and memory impairments. As the underlying causes of such conditions are very heterogeneous, manipulations that can enhance learning and memory in mice under different circumstances might be able to overcome the cognitive deficits in patients. The M-current regulates neuronal excitability and action potential firing, suggesting that its inhibition may increase cognitive capacities. We demonstrate that XE991, a specific M-current blocker, enhances learning and memory in healthy mice. This effect may be achieved by altering basal hippocampal synaptic activity and by diminishing the stimulation threshold for long-term changes in synaptic efficacy and learning-related gene expression. We also show that training sessions regulate the M-current by transiently decreasing the levels of KCNQ/Kv7.3 protein, a pivotal subunit for the M-current. Furthermore, we found that XE991 can revert the cognitive impairment associated with acetylcholine depletion and the neurodegeneration induced by kainic acid. Together, these results show that inhibition of the M-current as a general strategy may be useful to enhance cognitive capacities in healthy and aging individuals, as well as in those with neurodegenerative diseases. (C) 2009 Wiley-Liss, Inc.