Presenilins are essential for regulating neurotransmitter release.
Presenilins are essential for regulating neurotransmitter release.
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DOI：
10.1038/nature08177
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发表时间：
2009-07-30
期刊：
影响因子：
64.8
通讯作者：
Shen, Jie
中科院分区：
文献类型：
--
作者：
Zhang, Chen;Wu, Bei;Beglopoulos, Vassilios;Wines-Samuelson, Mary;Zhang, Dawei;Dragatsis, Ioannis;Suedhof, Thomas C.;Shen, Jie
早老素基因突变是家族性阿尔茨海默病（AD）的主要原因。早老素活性的丧失和/或淀粉样蛋白-β肽的积累已被提出通过损害突触功能介导AD的发病机制。然而，突触功能障碍的确切位置和性质尚不清楚。在这里，我们采用遗传方法在海马Schaeffer-collateral通路的突触前（CA3）或突触后（CA1）神经元中有条件地灭活早老素。我们发现，由θ波刺激引起的长期增强（LTP）在突触前而非突触后的早老素缺失后减少。此外，早老素的突触前失活而非突触后失活改变了短期可塑性和突触促进。用开放通道NMDA受体拮抗剂MK-801测量，诱发谷氨酸释放的概率通过突触前早老素失活而降低。引人注目的是，内质网Ca2+储存的耗竭或ryanodine受体抑制剂对Ca2+释放的阻断模拟并阻断了突触前早老素失活的影响。总之，这些结果揭示了早老素在神经递质释放的活性依赖性调节和LTP诱导中通过调节突触前终末细胞内Ca2+释放的选择性作用，并进一步表明突触前功能障碍可能是导致阿尔茨海默病痴呆和神经退行性变的早期致病事件。
Mutations in the presenilin genes are the major cause of familial Alzheimer's disease (AD). Loss of presenilin activity and/or accumulation of amyloid-β peptides have been proposed to mediate the pathogenesis of AD by impairing synaptic function. However, the precise site and nature of the synaptic dysfunction remain unknown. Here we employ a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. We found that long-term potentiation (LTP) induced by theta burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, presynaptic but not postsynaptic inactivation of presenilins alters short-term plasticity and synaptic facilitation. The probability of evoked glutamate release, measured with the open-channel NMDA receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Strikingly, depletion of endoplasmic reticulum Ca2+-stores by thapsigargin or blockade of Ca2+-release from these stores by ryanodine receptor inhibitors mimics and occludes the effects of presynaptic presenilin inactivation. Collectively, these results reveal a selective role for presenilins in the activity-dependent regulation of neurotransmitter release and LTP induction via modulation of intracellular Ca2+-release in presynaptic terminals, and further suggest that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in AD.
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影响因子：
16.2
作者：
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通讯作者：
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