β-Amyloid inhibits E-S potentiation through suppression of cannabinoid receptor 1-dependent synaptic disinhibition.
β-Amyloid inhibits E-S potentiation through suppression of cannabinoid receptor 1-dependent synaptic disinhibition.
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DOI：
10.1016/j.neuron.2014.04.039
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发表时间：
2014-06-18
期刊：
影响因子：
16.2
通讯作者：
Madison DV
中科院分区：
文献类型：
--
作者：
Orr AL;Hanson JE;Li D;Klotz A;Wright S;Schenk D;Seubert P;Madison DV
β-淀粉样肽（Aβ）阻断海马突触的长时程增强（LTP）已被广泛报道。在这里，我们证明了Aβ更有效地阻断兴奋性突触后电位（EPSP）-锋电位耦合（E-S增强）的增强。这不是通过对兴奋性突触或突触后神经元的直接作用发生的，而是通过一种新的间接机制：减少内源性大麻素介导的强直周围去抑制。在高频（强直）刺激期间，内源性大麻素抑制体细胞突触抑制。我们发现Aβ阻止了内源性大麻素介导的去抑制，从而在强直刺激期间使突触抑制更加完整。这种完整的抑制作用对抗强直发作时海马锥体神经元的正常去极化，从而对抗突触可塑性的诱导。因此，确定了一种新的途径，通过该途径Aβ可以调节神经活动，与学习和记忆相关，以及它如何介导阿尔茨海默病中观察到的认知下降。
It has been widely reported that β-amyloid peptide (Aβ) blocks long-term potentiation (LTP) of hippocampal synapses. Here we show evidence that Aβ more potently blocks the potentiation of excitatory post-synaptic potential (EPSP) -spike coupling (E-S potentiation). This occurs not by direct effect on excitatory synapses or postsynaptic neurons, but rather through a novel indirect mechanism: reduction of endocannabinoid-mediated peri-tetanic disinhibition. During high frequency (tetanic) stimulation, somatic synaptic inhibition is suppressed by endocannabinoids. We find that Aβ prevents this endocannabinoid-mediated disinhibition, thus leaving synaptic inhibition more intact during tetanic stimulation. This intact inhibition opposes the normal depolarization of hippocampal pyramidal neurons that occurs during tetanus, thus opposing the induction of synaptic plasticity. Thus, a novel pathway through which Aβ can act to modulate neural activity is identified, relevant to learning and memory and how it may mediate aspects of the cognitive decline seen in Alzheimer's disease.
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