Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Neurochem Int. 2018 Oct;119:120-125. doi: 10.1016/j.neuint.2017.09.009. Epub 2017 Sep 28.
It has been well accepted that d-serine may be an exclusive endogenous coagonist for the N-methyl-d-aspartate (NMDA)-type glutamate receptor in mammalian forebrain regions. We have recently found by using an in vivo dialysis method that an intra-medial prefrontal cortex infusion of S-α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (S-AMPA), a selective AMPA-type glutamate receptor agonist, causes a reduction in the extracellular levels of d-serine in a calcium-permeable AMPA receptor antagonist-sensitive manner. The inhibitory influence by the AMPA receptor on the extracellular d-serine, however, contradicts the data obtained from in vitro experiments that the AMPA receptor stimulation leads to facilitation of the d-serine liberation. This discrepancy appears to be due to the different cell setups between the in vivo and in vitro preparations. From the viewpoints of the previous reports indicating (1) the neuronal presence of d-serine synthesizing enzyme, serine racemase, and d-serine-like immunoreactivity and (2) the same high tissue concentrations of d-serine in the glia-enriched white matter and in the neuron-enriched gray matter of the mammalian neocortex, we have now investigated in the mouse medial prefrontal cortex, the effects of attenuation of neuronal and glial activities, by tetrodotoxin or fluorocitrate, respectively, on the S-AMPA-induced downregulation of the extracellular d-serine contents. In vivo dialysis studies revealed that a local infusion of tetrodotoxin or fluorocitrate eliminated the ability of S-AMPA given intra-cortically to cause a significant decrease in the dialysate concentrations of d-serine without affecting the elevating effects of S-AMPA on those of glycine, another intrinsic coagonist for the NMDA receptor. These findings suggest that the control by the AMPA receptor of the extracellular d-serine levels could be modulated by the neuronal and glial activities in the prefrontal cortex. It cannot be excluded that fluorocitrate would indirectly alter the modulation by changing synaptic neurotransmission via glial activity attenuation as previously reported.
人们普遍认为 D-丝氨酸可能是哺乳动物前脑区域 N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体的独特内源性共激动剂。我们最近通过使用体内透析方法发现，内侧前额叶皮质中 S-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（S-AMPA）的输注，一种选择性 AMPA 型谷氨酸受体激动剂，以钙通透性 AMPA 受体拮抗剂敏感的方式降低细胞外 D-丝氨酸的水平。然而，AMPA 受体对细胞外 D-丝氨酸的抑制作用与从体外实验中获得的数据相矛盾，即 AMPA 受体的刺激导致 D-丝氨酸释放的促进。这种差异似乎是由于体内和体外制剂之间的不同细胞设置造成的。从之前的报告表明（1）神经元存在 D-丝氨酸合成酶，丝氨酸消旋酶和 D-丝氨酸样免疫反应性，以及（2）哺乳动物新皮质的富含胶质的白质和富含神经元的灰质中的 D-丝氨酸具有相同的高组织浓度这两个观点来看，我们现在在小鼠内侧前额叶皮质中研究了分别用河豚毒素或氟柠檬酸减弱神经元和胶质活性对 S-AMPA 诱导的细胞外 D-丝氨酸含量下调的影响。体内透析研究表明，局部输注河豚毒素或氟柠檬酸消除了皮质内给予 S-AMPA 引起 D-丝氨酸透析液浓度显著降低的能力，而不影响 S-AMPA 对另一种 NMDA 受体内源性共激动剂甘氨酸的升高作用。这些发现表明，AMPA 受体对细胞外 D-丝氨酸水平的控制可以通过前额叶皮质中的神经元和胶质活性来调节。不能排除氟柠檬酸会通过先前报道的通过胶质活性减弱改变突触神经传递来间接改变调制作用。
