CEINGE Biotecnologie Avanzate, Via Comunale Margherita, 482 - 80145, Naples, Italy.
Neurobiol Aging. 2011 Dec;32(12):2229-43. doi: 10.1016/j.neurobiolaging.2010.01.002. Epub 2010 Jan 25.
Until recently, free d-amino acids were thought to be involved only in bacterial physiology. Nevertheless, today there is evidence that D-serine, by acting as co-agonist at NMDARs, plays a role in controlling neuronal functions in mammals. Besides D-serine, another D-amino acid, D-aspartate (D-Asp), is found in the mammalian brain with a temporal gradient of occurrence: high in embryo and low in adult. In this study, we demonstrate that D-Asp acts as an endogenous NMDAR agonist, since it triggers currents via interaction with each of NR2A-D receptor subunits. According to its pharmacological features, we showed that oral administration of D-Asp strongly enhances NMDAR-dependent LTP in adulthood and, in turn, completely rescues the synaptic plasticity decay observed in the hippocampus of aged animals. Therefore, our findings suggest a tantalizing hypothesis for which this in-embryo-occurring D-amino acid, when "forced" over its physiological content, may disclose plasticity windows inside which it counteracts the age-related reduction of NMDAR signaling.
直到最近，人们还认为游离 D-氨基酸只参与细菌生理学。然而，如今有证据表明，D-丝氨酸作为 NMDAR 的协同激动剂，在控制哺乳动物神经元功能方面发挥作用。除了 D-丝氨酸，另一种 D-氨基酸 D-天冬氨酸 (D-Asp) 也存在于哺乳动物大脑中，其出现具有时间梯度：在胚胎中含量高，在成年中含量低。在这项研究中，我们证明 D-Asp 作为一种内源性 NMDAR 激动剂发挥作用，因为它通过与每个 NR2A-D 受体亚基相互作用触发电流。根据其药理学特征，我们表明 D-Asp 的口服给药可在成年期强烈增强 NMDAR 依赖性 LTP，并且反过来完全挽救了在老年动物海马体中观察到的突触可塑性下降。因此，我们的发现提出了一个诱人的假设，即在胚胎中出现的这种 D-氨基酸，如果“强制”超过其生理含量，可能会揭示其中的可塑性窗口，在这些窗口中，它可以对抗与年龄相关的 NMDAR 信号转导减少。
