Differential regulation of NMDA receptors by d-serine and glycine in mammalian spinal locomotor networks.
Differential regulation of NMDA receptors by d-serine and glycine in mammalian spinal locomotor networks.
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DOI：
10.1152/jn.00810.2016
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发表时间：
2017-05-01
影响因子：
2.5
通讯作者：
Miles GB
中科院分区：
文献类型：
--
作者：
Acton D;Miles GB
我们提供的证据表明，小鼠脊髓运动网络内的NMDARs确定正在进行的运动相关活动的频率和幅度在体外和NMDARs的调节由d-丝氨酸和甘氨酸在突触特异性和活动依赖性的方式。此外，甘氨酸转运蛋白-1被证明是一个重要的调节NMDAR在运动相关的活动。这些结果表明，兴奋性传输可以调整，以多样化的输出剧目的脊髓运动网络在哺乳动物。N-甲基-d-天冬氨酸受体（NMDAR）的激活需要除谷氨酸之外的凝血剂（d-丝氨酸或甘氨酸）的结合。凝血因子结合位点的占用率的变化，建议调制神经网络，包括那些控制青蛙蝌蚪游泳。在这里，我们表征哺乳动物脊髓运动网络中的NMDAR凝血因子结合位点的调节。通过d（−）-2-氨基-5-膦酰基戊酸（d-APV）或5，7-二氯犬尿烯酸阻断NMDAR，可降低新生小鼠脊髓前根中记录到的脊髓诱发运动相关活动的频率和幅度。此外，d-APV取消同步活动引起的抑制性传输的封锁。这些结果证明了NMDAR在小鼠运动网络中的重要作用。维生素C应用的d-丝氨酸增强了运动相关的频率，但不解除抑制的爆发，表明凝血结合位点饱和，在后者，但不是前者的活动模式。d-氨基酸氧化酶或丝氨酸外消旋酶抑制剂赤-β-羟基-l-天冬氨酸（HOAsp）消耗内源性d-丝氨酸会增加运动相关活动的频率，而应用l-丝氨酸来增强内源性d-丝氨酸合成会降低爆发频率，这表明抑制性中间神经元上的突触子集需要d-丝氨酸。与此一致，HOAsp在活性解除抑制期间无效。应用甘氨酸（1-100 µM）未能改变运动相关活性，而甘氨酸转运蛋白-1（GlyT 1）的选择性抑制剂ALX 5407可增强爆发频率，支持GlyT 1在NMDAR调节中的作用。总之，这些发现表明脊髓运动网络内的凝血结合位点的活性依赖性和突触特异性调节，说明NMDAR调节在塑造运动输出中的重要性。新&值得注意的是，我们提供的证据表明，在小鼠脊髓运动网络内的NMDARs确定正在进行的运动相关的活动在体外的频率和幅度，NMDARs的调节由d-丝氨酸和甘氨酸在突触特异性和活动依赖性的方式。此外，甘氨酸转运蛋白-1被证明是一个重要的调节NMDAR在运动相关的活动。这些结果表明，兴奋性传输可以调整，以多样化的输出剧目的脊髓运动网络在哺乳动物。
We provide evidence that NMDARs within murine spinal locomotor networks determine the frequency and amplitude of ongoing locomotor-related activity in vitro and that NMDARs are regulated by d-serine and glycine in a synapse-specific and activity-dependent manner. In addition, glycine transporter-1 is shown to be an important regulator of NMDARs during locomotor-related activity. These results show how excitatory transmission can be tuned to diversify the output repertoire of spinal locomotor networks in mammals. Activation of N-methyl-d-aspartate receptors (NMDARs) requires the binding of a coagonist, either d-serine or glycine, in addition to glutamate. Changes in occupancy of the coagonist binding site are proposed to modulate neural networks including those controlling swimming in frog tadpoles. Here, we characterize regulation of the NMDAR coagonist binding site in mammalian spinal locomotor networks. Blockade of NMDARs by d(−)-2-amino-5-phosphonopentanoic acid (d-APV) or 5,7-dichlorokynurenic acid reduced the frequency and amplitude of pharmacologically induced locomotor-related activity recorded from the ventral roots of spinal-cord preparations from neonatal mice. Furthermore, d-APV abolished synchronous activity induced by blockade of inhibitory transmission. These results demonstrate an important role for NMDARs in murine locomotor networks. Bath-applied d-serine enhanced the frequency of locomotor-related but not disinhibited bursting, indicating that coagonist binding sites are saturated during the latter but not the former mode of activity. Depletion of endogenous d-serine by d-amino acid oxidase or the serine-racemase inhibitor erythro-β-hydroxy-l-aspartic acid (HOAsp) increased the frequency of locomotor-related activity, whereas application of l-serine to enhance endogenous d-serine synthesis reduced burst frequency, suggesting a requirement for d-serine at a subset of synapses onto inhibitory interneurons. Consistent with this, HOAsp was ineffective during disinhibited activity. Bath-applied glycine (1–100 µM) failed to alter locomotor-related activity, whereas ALX 5407, a selective inhibitor of glycine transporter-1 (GlyT1), enhanced burst frequency, supporting a role for GlyT1 in NMDAR regulation. Together these findings indicate activity-dependent and synapse-specific regulation of the coagonist binding site within spinal locomotor networks, illustrating the importance of NMDAR regulation in shaping motor output. NEW & NOTEWORTHY We provide evidence that NMDARs within murine spinal locomotor networks determine the frequency and amplitude of ongoing locomotor-related activity in vitro and that NMDARs are regulated by d-serine and glycine in a synapse-specific and activity-dependent manner. In addition, glycine transporter-1 is shown to be an important regulator of NMDARs during locomotor-related activity. These results show how excitatory transmission can be tuned to diversify the output repertoire of spinal locomotor networks in mammals.