Glutamate is required for depression but not potentiation of long-term presynaptic function.
Glutamate is required for depression but not potentiation of long-term presynaptic function.
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DOI：
10.7554/elife.29688
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发表时间：
2017-11-15
期刊：
影响因子：
7.7
通讯作者：
Emptage N
中科院分区：
文献类型：
--
作者：
Padamsey Z;Tong R;Emptage N
河豚的可塑性被认为需要谷氨酸信号。我们表明，这不是海马体突触前长时程增强(LTPpre)的情况，它表现为递质释放概率(Pr)的增加。我们发现，在没有谷氨酸信号的情况下，LTPpre可以通过突触前和突触后峰的配对来诱导。LTPpre的诱导涉及逆行一氧化氮信号的非规范机制，该机制由L型电压门控钙通道的钙离子内流触发，而不是突触后NMDAR，不需要谷氨酸释放。当谷氨酸释放时，它通过激活突触前NMDAR来减少PR，并促进突触前的长期抑制。因此，Pr的净变化取决于两个相反的因素：(1)Hebbian活性，它增加Pr；(2)谷氨酸释放，它降低Pr。因此，Hebbian活动过程中的释放失败促进了LTPpre的诱导。我们的发现揭示了一个新的突触前可塑性框架，它与传统的突触后可塑性模型有根本的不同。神经元之间在称为突触的连接处相互通信。突触处的一个神经元释放一种名为神经递质的化学物质，它与另一个神经元结合并激活。因此，神经递质的释放使一个细胞的电活动能够影响另一个细胞的电活动。这种交流的效率可能会随着时间的推移而变化，就像人们认为的在学习过程中发生的那样。如果突触两侧的神经元同时反复活跃，神经元相互传递电信号的能力就会增强。如果第一个神经元变得更有可能释放神经递质，神经元之间的交流就会变得更有效率。大脑中的大多数突触释放一种名为谷氨酸的神经递质，大多数类型的学习涉及谷氨酸能突触沟通效率的变化。但谷氨酸的释放并不可靠。活跃的谷氨酸能神经元大约80%的时间不能释放谷氨酸。如果谷氨酸在学习中起着关键作用，那么在谷氨酸释放如此不可能的情况下，大脑如何有效地学习呢？为了找出答案，帕达姆西等人。研究了小鼠和大鼠大脑组织切片中的谷氨酸能突触。当突触上的两个神经元同时反复活动时，第一个神经元有时会更有可能释放谷氨酸。但这只发生在突触中，在突触中，第一个神经元通常一开始就无法释放谷氨酸。这表明，沟通障碍有助于推动突触的变化。当经常同时活跃的两个神经元不能有效通信时，这种故障会触发分子变化，使未来的通信更可靠。此前的研究结果表明，当谷氨酸释放时，突触会发生变化。目前的结果表明，当情况不变时，它们也会发生变化。这意味着，尽管神经元之间频繁发生通信故障，大脑仍能继续学习。包括阿尔茨海默病在内的许多神经系统疾病都会在突触处显示谷氨酸信号的改变。Padamsey等人。希望对这一过程的更好理解将导致这些疾病的新疗法。
Hebbian plasticity is thought to require glutamate signalling. We show this is not the case for hippocampal presynaptic long-term potentiation (LTPpre), which is expressed as an increase in transmitter release probability (Pr). We find that LTPpre can be induced by pairing pre- and postsynaptic spiking in the absence of glutamate signalling. LTPpre induction involves a non-canonical mechanism of retrograde nitric oxide signalling, which is triggered by Ca2+ influx from L-type voltage-gated Ca2+ channels, not postsynaptic NMDA receptors (NMDARs), and does not require glutamate release. When glutamate release occurs, it decreases Pr by activating presynaptic NMDARs, and promotes presynaptic long-term depression. Net changes in Pr, therefore, depend on two opposing factors: (1) Hebbian activity, which increases Pr, and (2) glutamate release, which decreases Pr. Accordingly, release failures during Hebbian activity promote LTPpre induction. Our findings reveal a novel framework of presynaptic plasticity that radically differs from traditional models of postsynaptic plasticity. Neurons communicate with one another at junctions called synapses. One neuron at the synapse releases a chemical substance called a neurotransmitter, which binds to and activates the other neuron. The release of neurotransmitter thus enables the electrical activity of one cell to influence the electrical activity of another. The efficiency of this communication can change over time, as is thought to occur during learning. If the neurons on both sides of a synapse are repeatedly active at the same time, the ability of the neurons to transmit electrical signals to each other increases. One way that communication between neurons can become more efficient is if the first neuron becomes more likely to release neurotransmitter. Most synapses in the brain release a neurotransmitter called glutamate, and most types of learning involve changes in the efficiency of communication at glutamatergic synapses. But glutamate release is unreliable. Active glutamatergic neurons fail to release glutamate about 80% of the time. If glutamate has a key role in learning, how does the brain learn efficiently when glutamate release is so unlikely? To find out, Padamsey et al. studied glutamatergic synapses in slices of tissue from mouse and rat brains. When both neurons at a synapse were repeatedly active at the same time, the first neuron would sometimes become more likely to release glutamate. But this only happened at synapses in which the first neuron usually failed to release glutamate in the first place. This suggests that communication failures help to drive change at synapses. When two neurons that are often active at the same time do not communicate efficiently, this failure triggers molecular changes that make future communication more reliable. Previous results have shown that synapses can change when glutamate release occurs. The current results show that they can also change when it does not. This means that the brain can continue to learn despite frequent communication failures between neurons. Many neurological disorders, including Alzheimer’s disease, show altered glutamate signalling at synapses. Padamsey et al. hope that a better understanding of this process will lead to new therapies for these disorders.