The NMDA receptor activation by D-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle
The NMDA receptor activation by D-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle
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DOI：
10.1073/pnas.1909458116
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发表时间：
2019-10-08
影响因子：
11.1
通讯作者：
Wolosker, Herman
中科院分区：
文献类型：
--
作者：
Neame, Samah;Safory, Hazem;Wolosker, Herman
星形胶质细胞表达从葡萄糖合成L-丝氨酸所需的3-磷酸甘油酸脱氢酶（Phgdh）。有人提出星形胶质细胞L-丝氨酸通过穿梭于神经元以维持D-丝氨酸的产生来调节NMDAR活性，但这一假设尚未得到验证。我们现在报告说，抑制星形胶质细胞Phgdh抑制从头合成的L-和D-丝氨酸和减少NMDAR突触电位和长时程增强（LTP）在Schaffer侧支-CA 1突触。同样地，细胞外L-丝氨酸的酶促去除损害LTP，支持神经胶质细胞和神经元之间的L-丝氨酸穿梭机制，产生NMDAR促凝剂D-丝氨酸。此外，删除丝氨酸消旋酶（SR）在amatergic神经元废除D-丝氨酸合成的Phgdh抑制相同的程度，这表明神经元是新合成的D-丝氨酸的主要来源。我们还发现，成年SR敲除（KO）小鼠的突触NMDAR激活需要Phgdh衍生的甘氨酸，尽管由于甘氨酸裂解系统的出现，出生后甘氨酸水平急剧下降。出乎意料的是，我们还发现甘氨酸通过双重机制调节D-丝氨酸代谢。第一个由紧张性抑制SR细胞内甘氨酸在体外观察，原代培养，和在体内微透析。第二个涉及短暂的甘氨酸诱导的D-丝氨酸释放通过Asc-1转运蛋白，废除在Asc-1 KO小鼠和减少删除SR在多巴胺能神经元的影响。我们的观察结果表明，甘氨酸是一个多方面的调节D-丝氨酸代谢和牵连D-丝氨酸和甘氨酸介导的NMDAR突触激活在成熟的海马通过Phgdh依赖的穿梭机制。
Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of L-serine from glucose. Astrocytic L-serine was proposed to regulate NMDAR activity by shuttling to neurons to sustain D-serine production, but this hypothesis remains untested. We now report that inhibition of astrocytic Phgdh suppressed the de novo synthesis of L-and D-serine and reduced the NMDAR synaptic potentials and long-term potentiation (LTP) at the Schaffer collaterals-CA1 synapse. Likewise, enzymatic removal of extracellular L-serine impaired LTP, supporting an L-serine shuttle mechanism between glia and neurons in generating the NMDAR coagonist D-serine. Moreover, deletion of serine racemase (SR) in glutamatergic neurons abrogated D-serine synthesis to the same extent as Phgdh inhibition, suggesting that neurons are the predominant source of the newly synthesized D-serine. We also found that the synaptic NMDAR activation in adult SR-knockout (KO) mice requires Phgdh-derived glycine, despite the sharp decline in the postnatal glycine levels as a result of the emergence of the glycine cleavage system. Unexpectedly, we also discovered that glycine regulates D-serine metabolism by a dual mechanism. The first consists of tonic inhibition of SR by intracellular glycine observed in vitro, primary cultures, and in vivo microdialysis. The second involves a transient glycine-induce D-serine release through the Asc-1 transporter, an effect abolished in Asc-1 KO mice and diminished by deleting SR in glutamatergic neurons. Our observations suggest that glycine is a multifaceted regulator of D-serine metabolism and implicate both D-serine and glycine in mediating NMDAR synaptic activation at the mature hippocampus through a Phgdh-dependent shuttle mechanism.