Errico F, D'Argenio V, Sforazzini F, Iasevoli F, Squillace M, Guerri G, Napolitano F, Angrisano T, Di Maio A, Keller S, Vitucci D, Galbusera A, Chiariotti L, Bertolino A, de Bartolomeis A, Salvatore F, Gozzi A, Usiello A
1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
Transl Psychiatry. 2015 Feb 17;5(2):e512. doi: 10.1038/tp.2015.2.
Increasing evidence points to a role for dysfunctional glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D-aspartate imbalance previously described. To investigate whether altered D-aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo(-)(/-)), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo(-/-) mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo(-/-) animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D-aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia.
越来越多的证据表明，功能失调的谷氨酸N-甲基-D-天冬氨酸受体（NMDAR）神经传递在精神分裂症中起作用。D-天冬氨酸是一种非典型氨基酸，通过与GluN2亚基上的谷氨酸位点结合来激活NMDAR。D-天冬氨酸在哺乳动物胚胎脑中大量存在，出生后由于D-天冬氨酸氧化酶（DDO）的活性而迅速减少。D-天冬氨酸对NMDAR的激动活性及其在神经发育过程中的出现，使这种D-氨基酸成为精神分裂症中观察到的一些与NMDAR相关改变的潜在介质。一致地，最近在精神分裂症患者的死后前额叶皮质中观察到D-天冬氨酸和NMDA的大量减少。在这里，我们表明精神分裂症患者前额叶样本中DDO mRNA表达增加，从而提示了一个合理的分子事件，可解释先前描述的D-天冬氨酸失衡。为了研究D-天冬氨酸水平的改变是否能调节与精神分裂症相关的神经回路和行为，我们还测量了NMDAR拮抗剂苯环己哌啶在Ddo基因敲除小鼠（Ddo(-)(/-)）中产生的拟精神病效应，该动物模型自围产期起D-天冬氨酸水平就持续升高。我们发现，与对照组相比，Ddo(-/-)小鼠由苯环己哌啶诱导的运动亢进和前脉冲抑制缺陷显著降低。此外，我们发现Ddo(-/-)动物中升高的D-天冬氨酸水平可显著抑制苯环己哌啶激活的功能回路，并影响可能参与精神分裂症的皮质-海马连接网络的发育。总的来说，目前的结果表明，D-天冬氨酸水平的改变可影响与精神分裂症相关的神经发育脑过程。
