Presynaptic receptors, by virtue of their locations, are ideally suited to influence the efficacy of synaptic transmission by affecting neurotransmitter release [58]. In the nervous system, action potential invasion of presynaptic terminals results in a characteristic series of events: initial Ca entry, followed by the activation of presynaptic vesicular release machinery, vesicular fusion, and the release of neurotransmitter into the synaptic cleft [103,105]. The efficacy of synaptic transmission is thus governed by the probability of neurotransmitter release, the amount of transmitter released from the presynaptic terminal, the type and number of postsynaptic neurotransmitter receptors, and their response to the released transmitter. Short- and long-term activity-dependent modulation of the efficacy of a synapse can proceed via a multitude of signaling mechanisms that impact on either the presynaptic release or the receptors that mediate postsynaptic responses [13,66,102]. Such modulatory mechanisms will be crucial for regulating the flow of information throughout the nervous system and have been implicated in many neural processes including learning and memory, vision, motor control, and neuroprotection. Modulation of transmitter release at a synapse was first demonstrated in the classical studies of Dudel and Kuffler [30] and Eccles [33] who identified that presynaptic GABA receptors inhibited transmitter release from crustacean motor neuron terminals and vertebrate sensory neuron terminals in the spinal cord, respectively. Since then, the modulation of transmitter release by presynaptic receptors is an accepted signaling pathway, and although the focus of attention initially fell on G-protein coupled receptors [52,94], it soon became clear that numerous populations of presynaptic receptors are equally important [53,58,67]. One receptor that has not featured prominently as a presynaptic regulator of transmitter release is the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor. It was first proposed to have a presynaptic locus of expression after it was found that exogenously applied NMDA facilitated the release of tritiated neurotransmitter from synaptosomes prepared from noradrenergic terminals in the hippocampus [86], cerebral cortex [37], and from dopaminergic terminals in the striatum [50,56,112]. Because of the nature of the preparations, these early studies failed to identify the exact loci of NMDA receptor (NMDAR) subunit expression. Further evidence for presynaptic NMDARs came from the pioneering work of Liu and colleagues [62] who identified NR1 subunit immunoreactivity in both the dorsal and ventral horns of the rat spinal cord, specifically on axon terminals and very near the active zone, indicating a direct role in the regulation of transmitter release. Similarly, immunoreactivity for NR1 and NR2 was found on presynaptic boutons in rat cerebellar cortex [82,83] and at mossy fiber CA synapses in monkey hippocampus [98]. These early findings provided the necessary impetus to find a more widespread role for presynaptic NMDARs in the regulation of neuronal signaling in the CNS. In this chapter, we discuss recent advances in our understanding of presynaptic NMDARs as important modulators of synaptic transmission. We consider the potential sources of glutamate for NMDAR activation; the downstream signaling mechanisms that ensue; and the differing forms of synaptic plasticity mediated by presynaptic NMDARs that undoubtedly help sculpt information processing in the brain.
突触前受体因其所处位置，非常适合通过影响神经递质释放来影响突触传递的效能[58]。在神经系统中，动作电位侵入突触前终末会引发一系列典型事件：首先是钙离子内流，随后是突触前囊泡释放机制的激活、囊泡融合以及神经递质释放到突触间隙[103,105]。因此，突触传递的效能受神经递质释放概率、从突触前终末释放的递质数量、突触后神经递质受体的类型和数量以及它们对释放递质的反应所支配。突触效能的短期和长期活动依赖性调节可通过多种信号传导机制进行，这些机制会影响突触前释放或介导突触后反应的受体[13,66,102]。此类调节机制对于调节整个神经系统的信息流至关重要，并且已涉及许多神经过程，包括学习与记忆、视觉、运动控制和神经保护。突触处递质释放的调节最早在杜德尔和库夫勒[30]以及埃克尔斯[33]的经典研究中得到证实，他们分别发现突触前γ-氨基丁酸（GABA）受体抑制甲壳类运动神经元终末和脊髓中脊椎动物感觉神经元终末的递质释放。从那时起，突触前受体对递质释放的调节就成为一种公认的信号传导途径，尽管最初注意力集中在G蛋白偶联受体上[52,94]，但很快就清楚众多类型的突触前受体同样重要[53,58,67]。一种尚未作为递质释放的突触前调节因子受到显著关注的受体是N-甲基-D-天冬氨酸（NMDA）敏感的谷氨酸受体。在发现外源性应用的NMDA促进从海马体中去甲肾上腺素能终末[86]、大脑皮层[37]以及纹状体中多巴胺能终末[50,56,112]制备的突触体释放氚标记的神经递质后，首次有人提出它具有突触前表达位点。由于实验制备的性质，这些早期研究未能确定NMDA受体（NMDAR）亚基表达的确切位点。突触前NMDAR的进一步证据来自刘及其同事的开创性工作[62]，他们在大鼠脊髓的背角和腹角中均鉴定出NR1亚基免疫反应性，具体位于轴突终末且非常靠近活性区，表明其在递质释放调节中具有直接作用。同样，在大鼠小脑皮层的突触前终扣[82,83]以及猴海马体的苔藓纤维CA突触[98]中发现了NR1和NR2的免疫反应性。这些早期发现为在中枢神经系统中寻找突触前NMDAR在神经元信号调节中的更广泛作用提供了必要的推动力。在本章中，我们将讨论我们对突触前NMDAR作为突触传递重要调节因子的理解的最新进展。我们将考虑NMDAR激活的谷氨酸潜在来源；随之而来的下游信号传导机制；以及由突触前NMDAR介导的不同形式的突触可塑性，这些无疑有助于塑造大脑中的信息处理过程。
