D-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801
D-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801
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DOI：
10.1523/jneurosci.1618-08.2008
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发表时间：
2008-10-08
影响因子：
5.3
通讯作者：
Usiello, Alessandro
中科院分区：
文献类型：
--
作者：
Errico, Francesco;Rossi, Silvia;Usiello, Alessandro
自从在哺乳动物中枢神经系统中发现以来，D-天冬氨酸和 D-丝氨酸引起了人们对其作为假定的神经调节分子的强烈兴趣。尽管 D-丝氨酸作为 NMDA 受体 (NMDAR) 内源性共激动剂的功能作用已被阐明，但 D-天冬氨酸在大脑中的生物学意义仍不清楚。在本研究中，我们证明非生理性高水平的 D-天冬氨酸 (1) 增加体内 NMDAR 活性，(2) 减弱安非他明和 MK-801 [(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]-环庚烯-5,10-亚胺马来酸氢]诱导的前脉冲抑制缺陷，(3) 产生谷氨酸的纹状体适应突触类似于长期氟哌啶醇治疗后观察到的突触，(4) 增强海马 NMDAR 依赖性记忆。这一证据是通过两种不同的实验策略获得的，这两种策略导致小鼠内源性 D-天冬氨酸水平异常增加：基于 D-天冬氨酸氧化酶基因靶向删除的遗传方法和基于口服 D-天冬氨酸的药理学方法。这项工作提供了 D-天冬氨酸对 NMDAR 信号传导发挥神经调节作用的体内证据，并提出了一个有趣的假设，即这种 D-氨基酸与 D-丝氨酸一样，可以用作治疗精神分裂症相关症状的治疗剂。
Since their discovery in the mammalian CNS, D-aspartate and D-serine have aroused a strong interest with regard to their role as putative neuromodulatory molecules. Whereas the functional role of D-serine as an endogenous coagonist of NMDA receptors (NMDARs) has been elucidated, the biological significance of D-aspartate in the brain is still mostly unclear. In the present study, we demonstrated that nonphysiological high levels of D-aspartate (1) increased in vivo NMDAR activity, (2) attenuated prepulse inhibition deficits induced by amphetamine and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate], (3) produced striatal adaptations of glutamate synapses resembling those observed after chronic haloperidol treatment, and (4) enhanced hippocampal NMDAR-dependent memory. This evidence was obtained using two different experimental strategies that produced an abnormal increase of endogenous D-aspartate levels in the mouse: a genetic approach based on the targeted deletion of the D-aspartate oxidase gene and a pharmacological approach based on oral administration of D-aspartate. This work provides in vivo evidence of a neuromodulatory role exerted by D-aspartate on NMDAR signaling and raises the intriguing hypothesis that also this D-amino acid, like D-serine, could be used as a therapeutic agent in the treatment of schizophrenia-related symptoms.