N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?
N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?
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DOI：
10.1016/j.brainresbull.2010.04.006
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发表时间：
2010-09-30
影响因子：
3.8
通讯作者：
Javitt DC
中科院分区：
文献类型：
--
作者：
Kantrowitz JT;Javitt DC
精神分裂症是一种严重的精神障碍，伴有一系列特征性症状和神经认知缺陷。目前，病因机制仍然相对未知，尽管近年来已经确定了多个汇合点。主要的汇聚点之一是N-甲基-D-天冬氨酸（NMDAR）型谷氨酸受体功能障碍。NMDAR拮抗剂产生的临床综合征与精神分裂症的阴性和认知症状非常相似，并且独特地结合了精神分裂症的阴性和认知症状，沿着在精神分裂症中观察到的神经认知功能障碍的特定模式。已经描述了涉及NMDAR亚基，特别是GRIN 2B亚基的遗传多态性。此外，在涉及NMDAR的调节系统中描述了多态性，包括调节脑D-丝氨酸合成的酶丝氨酸消旋酶和D-氨基酸氧化酶/G72。血浆和脑甘氨酸、D-丝氨酸和谷胱甘肽水平的降低也被描述，提供了NMDAR功能障碍的潜在机制。独特的NMDAR的特点，可以解释的特征模式的症状和神经认知功能障碍的精神分裂症。最后，NMDAR复合物代表了精神分裂症潜在新治疗方法的汇聚点，该方法旨在纠正变构调节剂合成和调节中的潜在异常，以及突触前和突触后神经递质和NMDAR功能的更普遍增强。
Schizophrenia is a severe mental disorder associated with a characteristic constellation of symptoms and neurocognitive deficits. At present, etiological mechanisms remain relatively unknown, although multiple points of convergence have been identified over recent years. One of the primary convergence points is dysfunction of N-methyl-D-aspartate (NMDAR)-type glutamate receptors. Antagonists of NMDAR produce a clinical syndrome that closely resembles, and uniquely incorporates negative and cognitive symptoms of schizophrenia, along with the specific pattern of neurocognitive dysfunction seen in schizophrenia. Genetic polymorphisms involving NMDAR subunits, particularly the GRIN2B subunit have been described. In addition, polymorphisms have been described in modulatory systems involving the NMDAR, including the enzymes serine racemase and D-amino acid oxidase/G72 that regulate brain D-serine synthesis. Reductions in plasma and brain glycine, D-serine and glutathione levels have been described as well, providing potential mechanisms underlying NMDAR dysfunction. Unique characteristics of the NMDAR are described that may explain the characteristic pattern of symptoms and neurocognitive deficits observed in schizophrenia. Finally, the NMDAR complex represents a convergence point for potential new treatment approaches in schizophrenia aimed at correcting underlying abnormalities in synthesis and regulation of allosteric modulators, as well as more general potentiation of pre- and post-synaptic glutamatergic and NMDAR function.
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