Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder
Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder
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DOI：
10.1038/sj.npp.1300451
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发表时间：
2004-07-01
影响因子：
7.6
通讯作者：
Meador-Woodruff, JH
中科院分区：
文献类型：
--
作者：
Clinton, SM;Meador-Woodruff, JH
多项研究支持精神分裂症中谷氨酸功能障碍的假说，包括我们最近关于老年精神分裂症患者丘脑中 NMDA 受体亚基和相关细胞内蛋白转录物改变的报告。在本研究中，我们使用原位杂交来测量斯坦利基金会神经病理学联盟第二个较年轻的队列（其中包括精神分裂症和情感障碍患者）中 NMDA 亚基（NRI、NR2A-D）和相关细胞内蛋白（NF-L、PSD95 和 SAP102）的表达。我们想要确定精神分裂症患者丘脑中的谷氨酸异常是否存在于较年轻的年龄，以及这些异常是否发生在其他精神疾病中。在目前的工作中，我们观察到精神分裂症中 NMDA NR2B 亚基转录物的表达增加，以及所有三种相关突触后密度蛋白转录物的表达减少。我们还发现了情感障碍（尤其是双相情感障碍）中丘脑谷氨酸功能障碍的证据。特别是，我们发现双相情感障碍中的 NF-L、PSD95 和 SAP102 转录物降低，重度抑郁症中的 SAP102 水平降低。有趣的是，各诊断组最一致的发现之一是与 NMDA 受体相关的细胞内信号分子异常，而不是受体亚基本身的变化。 PSD95 和类似的支架分子将 NMDA 受体与介导信号传导的细胞内酶连接起来，并在不同神经递质系统之间提供物理连接，以协调和整合来自多个效应器系统的信息。 PSD95 样分子和其他细胞内信号机制的异常可能导致多个神经递质系统（例如谷氨酸和多巴胺能系统）之间的通讯失调，这些神经递质系统可能参与精神分裂症和情感障碍的神经生物学。
Several lines of investigation support a hypothesis of glutamatergic dysfunction in schizophrenia, including our recent reports of altered NMDA receptor subunit and associated intracellular protein transcripts in the thalamus of elderly patients with schizophrenia. In the present study, we used in situ hybridization to measure the expression of NMDA subunits (NRI, NR2A-D) and associated intracellular proteins (NF-L, PSD95 and SAP102) in a second, younger cohort from the Stanley Foundation Neuropathology Consortium, which included patients with both schizophrenia and affective disorders. We wanted to determine whether glutamatergic abnormalities in the thalamus in schizophrenia are present at younger ages, and whether these abnormalities occur in other psychiatric illnesses, In the present work, we observed increased expression of NMDA NR2B subunit transcripts, and decreased expression of all three associated postsynaptic density protein transcripts in schizophrenia. We also found evidence of glutamatergic dysfunction in the thalamus in affective disorders, particularly in bipolar disorder. In particular, we found decreased NF-L, PSD95, and SAP102 transcripts in bipolar disorder, and decreased SAP102 levels in major depression. Interestingly, one of the most consistent findings across diagnostic groups was an abnormality of intracellular signaling molecules that are linked to the NMDA receptor, rather than changes in the receptor subunits themselves. PSD95 and similar scaffolding molecules link the NMDA receptor with intracellular enzymes that mediate signaling, and also provide a physical link between different neurotransmitter systems to coordinate and integrate information from multiple effector systems. Abnormalities of PSD95-like molecules and other intracellular signaling machinery may contribute to dysregulated communication between multiple neurotransmitter systems (such as glutamatergic and dopaminergic systems) that are potentially involved in the neurobiology of schizophrenia and affective disorders.