The free d-amino acid, d-aspartate, is abundant in the embryonic brain but significantly decreases after birth. Besides its intracellular occurrence, d-aspartate is also present at extracellular level and acts as an endogenous agonist for NMDA and mGlu5 receptors. These findings suggest that d-aspartate is a candidate signaling molecule involved in neural development, influencing brain morphology and behaviors at adulthood. To address this issue, we generated a knockin mouse model in which the enzyme regulating d-aspartate catabolism, d-aspartate oxidase (DDO), is expressed starting from the zygotic stage, to enable the removal of d-aspartate in prenatal and postnatal life. In line with our strategy, we found a severe depletion of cerebral d-aspartate levels (up to 95%), since the early stages of mouse prenatal life. Despite the loss of d-aspartate content, Ddo knockin mice are viable, fertile, and show normal gross brain morphology at adulthood. Interestingly, early d-aspartate depletion is associated with a selective increase in the number of parvalbumin-positive interneurons in the prefrontal cortex and also with improved memory performance in Ddo knockin mice. In conclusion, the present data indicate for the first time a biological significance of precocious d-aspartate in regulating mouse brain formation and function at adulthood.

中文翻译：

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产前D-天冬氨酸氧化酶的表达导致早期的脑D-天冬氨酸耗竭并影响成年期的脑形态和认知功能。

游离的d-氨基酸d-天门冬氨酸在胚胎脑中丰富，但出生后会明显减少。除其在细胞内的存在外，d-天冬氨酸也存在于细胞外水平，并作为NMDA和mGlu5受体的内源性激动剂。这些发现表明，d-天冬氨酸是参与神经发育，影响成年期大脑形态和行为的候选信号分子。为了解决这个问题，我们生成了一个敲入小鼠模型，其中从合子阶段开始表达调节d-天冬氨酸分解代谢的酶d-天冬氨酸氧化酶（DDO），从而能够去除d-参与产前和产后生活。根据我们的策略，自小鼠产前生命的早期以来，我们发现脑d-天门冬氨酸水平严重耗竭（高达95％）。尽管减少了d-天冬氨酸的含量，但Ddo敲除小鼠仍是有活力的，可育的，并且在成年后显示出正常的大脑形态。有趣的是，早期d-天冬氨酸耗竭与前额叶皮层中小白蛋白阳性的中间神经元数量的选择性增加有关，也与Ddo敲入小鼠的记忆能力提高有关。总之，本发明的数据首次表明早熟的生物学意义d-天冬氨酸调节成年小鼠大脑的形成和功能。