D-serine is synthesized by serine racemase (SR) and is a co-agonist at forebrain N-methyl-D-aspartate receptors (NMDARs). D-serine and SR are expressed primarily in neurons, but not in quiescent astrocytes. In this study, we examined the localization of D-serine and SR in the mouse striatum and the effects of genetically silencing SR expression in GABAergic interneurons (iSR-/-). iSR-/- mice had substantially reduced SR expression almost exclusively in striatum, but only exhibited marginal D-serine reduction. SR positive cells in the striatum showed strong co-localization with dopamine- and cyclic AMP-regulated neuronal phosphoprotein (DARPP32) in wild type mice. Transgenic fluorescent reporter mice for either the D1 or D2 dopamine receptors exhibited a 65:35 ratio for co-localization with D1and D2 receptor positive cells, respectively. These results indicate that GABAergic medium spiny neurons receiving dopaminergic inputs in striatum robustly and uniformly express SR. In behavioral tests, iSR-/- mice showed a blunted response to the hedonic and stimulant effects of cocaine, without affecting anxiety-related behaviors. Because the cocaine effects have been shown in the constitutive SR-/- mice, the restriction of the blunted response to cocaine to iSR-/- mice reinforces the conclusion that D-serine in striatal GABAergic neurons plays an important role in mediating dopaminergic stimulant effects. Results in this study suggest that SR in striatal GABAergic neurons is synthesizing D-serine, not as a glutamatergic co-transmitter, but rather as an autocrine whereby the GABAergic neurons control the excitability of their NMDARs by determining the availability of the co-agonist, D-serine.

中文翻译：

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纹状体神经元的丝氨酸消旋酶表达。

D-丝氨酸由丝氨酸消旋酶 (SR) 合成，是前脑 N-甲基-D-天冬氨酸受体 (NMDAR) 的共激动剂。D-丝氨酸和 SR 主要在神经元中表达，但不在静止星形胶质细胞中表达。在这项研究中，我们检查了 D-丝氨酸和 SR 在小鼠纹状体中的定位以及在 GABA 能中间神经元 (iSR-/-) 中基因沉默 SR 表达的影响。iSR-/- 小鼠几乎完全在纹状体中显着降低了 SR 表达，但仅表现出边缘 D-丝氨酸减少。纹状体中的 SR 阳性细胞在野生型小鼠中显示出与多巴胺和环 AMP 调节的神经元磷蛋白 (DARPP32) 的强烈共定位。D1 或 D2 多巴胺受体的转基因荧光报告小鼠分别以 65:35 的比例与 D1 和 D2 受体阳性细胞共定位。这些结果表明，在纹状体中接收多巴胺能输入的 GABA 能中型多刺神经元稳健且一致地表达 SR。在行为测试中，iSR-/- 小鼠对可卡因的享乐和兴奋作用表现出迟钝的反应，但不影响与焦虑相关的行为。由于可卡因效应已在组成型 SR-/- 小鼠中显示出来，因此限制 iSR-/- 小鼠对可卡因的迟钝反应强化了纹状体 GABA 能神经元中的 D-丝氨酸在介导多巴胺能兴奋剂作用中起重要作用的结论. 这项研究的结果表明，纹状体 GABA 能神经元中的 SR 正在合成 D-丝氨酸，而不是作为谷氨酸能共递质，而是作为一种自分泌，GABA 能神经元通过确定共激动剂的可用性来控制其 NMDARs 的兴奋性，