Unique transsynaptic complexes enable long-term synaptic plasticity in a synapse-specific manner.
Unique transsynaptic complexes enable long-term synaptic plasticity in a synapse-specific manner.
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DOI：
10.1073/pnas.2206429119
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发表时间：
2022-07-05
影响因子：
11.1
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中科院分区：
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突触传递的长时程增强（LTP）可能是神经科学中研究最多的细胞现象之一，是指通常由短暂的重复活动引起的突触连接的持久强化。这种现象的令人兴奋之处很大程度上依赖于早期的想法，即 LTP 可能是某些形式的学习和记忆的细胞相关性。尽管自 5 年前发现 LTP 以来，人们对其进行了深入的研究（PubMed 中列出了超过 17,000 篇出版物），但关于其分子机制和功能相关性仍然存在重要的知识差距。越来越多的证据表明，已知在突触发育中发挥关键作用的跨突触粘附复合物也与成熟突触的 LTP 有关，尽管其确切机制尚不清楚。最近发表在 PNAS 上的一项研究发现，一种跨突触蛋白质-蛋白质相互作用对于 LTP 至关重要，但对于基础诱发突触传递并非必需 (1)（图 1）。LTP 首次报道于齿状回（海马的主要入口区域），在内嗅皮质 (EC) 和颗粒细胞 (GC) 的锥体神经元之间建立的兴奋性突触处 (2)，但后来在其他几个地方也发现了这种相互作用。脊椎动物和无脊椎动物的突触。 LTP 并不是一个单一的现象。已经报道了兴奋性和抑制性突触的几种机制上不同的长期突触可塑性形式，并且学习不太可能依赖于单一形式的活动依赖性突触可塑性。然而，到目前为止，大多数研究都集中在“经典”形式的兴奋性 LTP（又名 Hebbian LTP）上，就像最初在 EC-GC 突触中发现的那样。在那里，神经递质谷氨酸短暂激活 N-甲基-D-天冬氨酸受体 (NMDAR) 导致钙离子流入，从而引发持久的突触强化，这很可能是由于突触后 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPAR) 的募集所致。 LTP 伴随着其他变化，例如突触大小的增加，并受到许多分子的调节。最近，与 LTP 相关的一长串分子名单中又增加了一个成员，其中包括跨突触粘附复合物。例如，neuroligin-1 和 LRRTM 这两种细胞粘附分子是突触前神经毒素 (Nrxn) 的突触后受体，是 CA3 至 CA1 锥体细胞突触处 LTP 诱导所必需的 (3)，但其他兴奋性突触是否也需要这些跨突触复合物仍不清楚。突触前 Nrxn 的其他突触后受体也与突触功能有关，包括谷氨酸受体 GluD1 和 GluD2。 GluD1 在大脑中广泛表达，是海马中正常 AMPAR 和 NMDAR 介导的突触传递所必需的 (4, 5)，而 GluD2 在浦肯野细胞中表达，是小脑中长期抑郁 (LTD) 所必需的 (6)。因此，与突触显着的分子多样性一致
Long-term potentiation (LTP) of synaptic transmission, possibly one of the most studied cellular phenomena in neuroscience, refers to the long-lasting strengthening of a synaptic connection typically induced by brief repetitive activity. Much of the excitement about this phenomenon relies on the early idea that LTP could be a cellular correlate of some forms of learning and memory. Despite intense research on LTP since its discovery five decades ago (> 17,000 publications listed in PubMed), important knowledge gaps remain regarding its molecular mechanisms and functional relevance. Growing evidence indicates that transsynaptic adhesion complexes known to play key roles in synapse development are also implicated in LTP at mature synapses, although the precise mechanism is poorly understood. A recent study published in PNAS has identified a transsynaptic protein–protein interaction that is essential for LTP but not for basal evoked synaptic transmission (1)(Fig. 1).LTP was first reported in the dentate gyrus, the main entry area of the hippocampus, at the excitatory synapse established between pyramidal neurons in the entorhinal cortex (EC) and granule cells (GC)(2), but it was later identified at several other synapses in vertebrates and invertebrates. LTP is not a unitary phenomenon. Several mechanistically distinct forms of long-term synaptic plasticity at both excitatory and inhibitory synapses have been reported, and it is unlikely that learning relies on a single form of activity-dependent synaptic plasticity. However, most studies, by far, have focused on a “classical” form of excitatory LTP (aka Hebbian LTP) like the one originally identified at EC–GC synapses. There, calcium influx via transient activation of N-methyl-D-aspartate receptors (NMDARs) by the neurotransmitter glutamate triggers a long-lasting synaptic strengthening that is most likely due to the postsynaptic recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). LTP is accompanied by other changes such as an increase in synapse size and is regulated by numerous molecules. A recent addition to the long list of molecules implicated in LTP includes transsynaptic adhesion complexes. For example, neuroligin-1 and LRRTMs, two cell adhesion molecules which are postsynaptic receptors for presynaptic neurexins (Nrxn), are required for LTP induction at CA3 to CA1 pyramidal cell synapses (3), but whether these transsynaptic complexes are also required at other excitatory synapses remains unclear. Other postsynaptic receptors for presynaptic Nrxn, which have also been implicated in synaptic function, include the glutamate receptors GluD1 and GluD2. GluD1 is widely expressed in the brain and is required for normal AMPAR-and NMDAR-mediated synaptic transmission in the hippocampus (4, 5), whereas GluD2 is expressed in Purkinje cells and is required for long-term depression (LTD) in the cerebellum (6). Thus, consistent with the remarkable molecular diversity of synapses
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影响因子：
5.5
作者：
BLISS, TVP;LOMO, T
通讯作者：
LOMO, T
影响因子：
34.7
作者：
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DOI：
10.1073/pnas.1802737115
发表时间：
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影响因子：
11.1
作者：
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5.3
作者：
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影响因子：
64.8
作者：
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